Antimicrobials and methods of making and using same

ABSTRACT

The present disclosure relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, reducing the risk of, and delaying the onset of microbial infections in humans and animals. 
     In some embodiments, the present disclosure provides a compound of Formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 62/681,498, filed Jun. 6, 2018; 62/660,782, filed Apr. 20, 2018;62/660,747, filed Apr. 20, 2018; 62/633,554, filed Feb. 21, 2018;62/633,454, filed Feb. 21, 2018; 62/593,445, filed Dec. 1, 2017;62/522,574, filed Jun. 20, 2017; and 62/521,835, filed Jun. 19, 2017,each of which is herein incorporated by reference in its entirety.

TECHNICAL FIELD

This invention relates to antimicrobial compounds, and more particularlyto pyrrolo[2,3-d]pyrimidin-2-ones useful for treating, preventing andreducing risk of microbial infections.

BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the1940s, many new compounds have been discovered or specifically designedfor use as antibiotic agents. It was once thought that infectiousdiseases could be completely controlled or eradicated with the use ofsuch therapeutic agents. However, such views have been challengedbecause strains of cells or microorganisms resistant to currentlyeffective therapeutic agents continue to evolve. Almost every antibioticagent developed for clinical use has ultimately encountered problemswith the emergence of resistant bacteria.

For example, resistant strains of Gram-positive bacteria such asmethicillin-resistant staphylococci, penicillin-resistant streptococci,and vancomycin-resistant enterococci have developed. Resistant bacteriacan cause serious and even fatal results for infected patients. See,e.g., Lowry, F. D. “Antimicrobial Resistance: The Example ofStaphylococcus aureus,” J. Clin. Invest., vol. 111, no. 9, pp. 1265-1273(2003); and Gold, H. S. and Moellering, R. C., Jr., “Antimicrobial-DrugResistance,” N. Engl. J. Med., vol. 335, pp. 1445-53 (1996).

The discovery and development of new antibacterial agents have been fordecades a major focus of many pharmaceutical companies. Nonetheless, inmore recent years there has been an exodus from this area of researchand drug development resulting in very few new antibiotics entering themarket. This lack of new antibiotics is particularly disturbing,especially at a time when bacterial resistance to current therapies isincreasing both in the hospital and community settings.

One approach to developing new antimicrobial compounds is to designmodulators, for example, inhibitors, of bacterial ribosome function. Bymodulating or inhibiting bacterial ribosome function, antimicrobialcompounds could interfere with essential processes such as RNAtranslation and protein synthesis, thereby providing an antimicrobialeffect. In fact, some antibiotic compounds such as erythromycin,clindamycin, and linezolid are known to bind to the ribosome.

SUMMARY

The present disclosure relates generally to the field of antimicrobialcompounds and to methods of making and using them. These compounds andtautomers thereof are useful for treating, preventing, reducing the riskof, or delaying the onset of microbial infections in humans and animals.The present disclosure also provides pharmaceutically acceptable saltsof these compounds and tautomers.

In some embodiments, the present application provides a compound ofFormula (AA):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

J is selected from

X is selected from a 5- or 6-membered heterocyclyl ring and phenyl,wherein each of the 5- or 6-membered heterocyclyl ring and the phenyl isoptionally substituted with one or more R^(X);

Z is selected from

R₁ is selected from H, C₁₋₃ alkyl, and C₂₋₄ alkenyl;

R₂ is selected from H and C₁₋₃ alkyl;

R₃ is selected from H and C₁₋₃ alkyl;

or R₂ and R₃ together with the nitrogen atoms to which they are attachedand the carbon atom connecting the two nitrogen atoms form a 5- or6-membered ring;

or R₂ and R₃ together with the nitrogen and sulfur atom to which theyare attached and the carbon atom connecting the two nitrogen atoms forma 5- or 6-membered ring;

R₄ is selected from H and C₁₋₃ alkyl;

R₅ is selected from H and C₁₋₆ alkyl;

R₆ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₃₋₆ cycloalkyl,wherein the C₁₋₆ alkyl is optionally substituted with one or moresubstituents selected from the group consisting of halogen, OR^(a),SR^(a), —C(O)OR^(a), —SC(NH)NH₂, C₃₋₆ cycloalkyl, and 3-6 memberedheterocyclyl;

R₇ is selected from H and C₁₋₆ alkyl;

or R₆ and R₇ together with the carbon and nitrogen atoms to which theyare attached form a ring having one of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH;

-   -   or R₅ and R₇ together with the carbon atoms to which they are        attached and the nitrogen atom connecting the two carbon atoms        form a ring having one of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withOH;

Q is selected from C₁₋₂ alkylene or —C(O)—;

R₂₁ is selected from H, C₁₋₆ alkyl optionally substituted with 1-3 halo;

R₈ is selected from H and halogen;

each R^(X) is independently selected from halogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆ cycloalkyl,and aryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore R^(b);

or two adjacent R^(X) come together with the atoms to which they areattached to form a 5- or 6-membered ring;

each R^(a) is independently selected from H and C₁₋₆ alkyl;

each R^(b) is independently selected from C₂₋₆ alkenyl, OR^(c),N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, OC(NH)NH₂, and aryl;

each R^(c) is independently selected from H, C₁₋₆ alkyl, aryl,—C(O)aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are eachoptionally substituted with one or more R^(d); and

each R^(d) is independently selected from C₁₋₃ alkyl, OH, O(C₁₋₃ alkyl),NO₂, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

Also provided herein is a compound of Formula (A):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

X is selected from a 5- or 6-membered heterocyclyl ring and phenyl,wherein each of the 5- or 6-membered heterocyclyl ring and phenyl isoptionally substituted with one or more R^(X);

Z is selected from

R₁ is selected from H and C₁₋₃ alkyl;

R₂ is selected from H and C₁₋₃ alkyl;

R₃ is selected from H and C₁₋₃ alkyl;

or R₂ and R₃ together with the nitrogen atoms to which they are attachedand the carbon atom connecting the two nitrogen atoms form a 5- or6-membered ring;

R₄ is selected from H and C₁₋₃ alkyl;

R₅ is selected from H and C₁₋₆ alkyl;

R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl is optionally substituted with one or more substituents selectedfrom the group consisting of halogen, OR^(a), SR^(a), —C(O)OR^(a),—SC(NH)NH₂, C₃₋₆ cycloalkyl, and 3-6 membered heterocyclyl;

R₇ is selected from H and C₁₋₆ alkyl;

or R₆ and R₇ together with the carbon and nitrogen atoms to which theyare attached form a ring having one of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH;

-   -   or R₅ and R₇ together with the carbon atoms to which they are        attached and the nitrogen atom connecting the two carbon atoms        form a ring having one of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withOH;

Q is selected from C₁₋₂ alkylene or —C(O)—;

R₂₁ is selected from H, C₁₋₆ alkyl optionally substituted with 1-3 halo;

R₈ is selected from H and halogen;

each R^(X) is independently selected from halogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆ cycloalkyl,and aryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore R^(b);

or two adjacent R^(X) come together with the atoms to which they areattached to form a 5- or 6-membered ring;

each R^(a) is independently selected from H and C₁₋₆ alkyl;

each R^(b) is independently selected from C₂₋₆ alkenyl, OR^(c),N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl;

each R^(c) is independently selected from H, C₁₋₆ alkyl, aryl,—C(O)aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are eachoptionally substituted with one or more R^(d); and

each R^(d) is independently selected from C₁₋₃ alkyl, OH, O(C₁₋₃ alkyl),NO₂, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

Also provided herein is a compound of Formula (I):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   X is selected from a 5- or 6-membered heterocyclyl ring and phenyl,    wherein each of the 5- or 6-membered heterocyclyl ring and the    phenyl is optionally substituted with one or more R^(X);-   R₁ is selected from H and C₁₋₃ alkyl;-   R₂ is selected from H and C₁₋₃ alkyl;-   R₃ is selected from H and C₁₋₃ alkyl;-   or R₂ and R₃ together with the nitrogen atoms to which they are    attached and the carbon atom connecting the two nitrogen atoms form    a 5- or 6-membered ring;-   R₄ is selected from H and C₁₋₃ alkyl;-   R₅ is selected from H and C₁₋₆ alkyl;-   R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the    C₁₋₆ alkyl is optionally substituted with one or more substituents    selected from the group consisting of halogen, OR^(a), SR^(a),    —C(O)OR^(a), —SC(NH)NH₂, C₃₋₆ cycloalkyl, and 3-6 membered    heterocyclyl;-   R₇ is selected from H and C₁₋₆ alkyl;-   or R₆ and R₇ together with the carbon and nitrogen atoms to which    they are attached form a ring having one of the formulas:

-   wherein the ring is optionally substituted on a ring carbon atom    with C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted    with one or more OH;-   or R₅ and R₇ together with the carbon atoms to which they are    attached and the nitrogen atom connecting the two carbon atoms form    a ring having one of the formulas:

-   R₈ is selected from H and halogen;-   each R^(X) is independently selected from halogen, C₁₋₆ alkyl, C₁₋₄    haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆    cycloalkyl, and aryl, wherein the C₁₋₆ alkyl is optionally    substituted with one or more R^(b);-   or two adjacent R^(X) come together with the atoms to which they are    attached to form a 5- or 6-membered ring;-   each R^(a) is independently selected from H and C₁₋₆ alkyl;-   each R^(b) is independently selected from C₂₋₆ alkenyl, OR^(c),    N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl;-   each R^(c) is independently selected from H, C₁₋₆ alkyl, aryl,    —C(O)aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are    each optionally substituted with one or more R^(d); and-   each R^(d) is independently selected from C₁₋₃ alkyl, OH, O(C₁₋₃    alkyl), NO2, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

Also provided herein is a compound of Formula (II):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   R₁ is selected from H and C₁₋₃ alkyl;-   R₂ is selected from H and C₁₋₃ alkyl;-   R₃ is selected from H and C₁₋₃ alkyl;-   or R₂ and R₃ together with the nitrogen atoms to which they are    attached and the carbon atom connecting the two nitrogen atoms form    a 5- or 6-membered ring;-   R₄ is selected from H and C₁₋₃ alkyl;-   R₅ is selected from H and C₁₋₆ alkyl;-   R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the    C₁₋₆ alkyl is optionally substituted with one or more substituents    selected from the group consisting of halogen, OR^(a), SR^(a),    —C(O)OR^(a), —SC(NH)NH₂, C₃₋₆ cycloalkyl, or C₃₋₆ heterocyclyl;-   R₇ is selected from H and C₁₋₆ alkyl;-   or R₆ and R₇ together with the carbon and nitrogen atoms to which    they are attached form a ring having one of the formulas:

-   wherein the ring is optionally substituted on a ring carbon atom    with C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted    with one or more OH;-   or R₅ and R₇ together with the carbon atoms to which they are    attached and the nitrogen atom connecting the two carbon atoms form    a ring having one of the formulas:

-   R₈ is selected from H and halogen;-   R₉ is selected from H and halogen;-   R₁₀ is selected from H, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and    C₃₋₆ cycloalkyl;-   R₁₁ is selected from C₁₋₃ alkyl, C₂₋₄ alkenyl, and C₃₋₆ cycloalkyl,    wherein the C₁₋₃ alkyl is optionally substituted with one or more    R^(b);-   R₁₇ is selected from H, halogen, and C₁₋₆ alkyl;-   each R^(a) is independently selected from H and C₁₋₆ alkyl;-   each R^(b) is independently selected from OR^(c), —C(O)OR^(c), and    —(O)aryl, wherein the aryl is optionally substituted with one or    more R^(d);-   each R^(c) is independently selected from hydrogen, C₁₋₃ alkyl, OH,    O(C₁₋₃ alkyl), NO₂, —C(O)aryl, and aryl; and-   each R^(d) is C₁₋₃ alkyl.

Also provided herein is a compound of Formula (III):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   R₁ is selected from H and C₁₋₃ alkyl;-   R₂ is selected from H and C₁₋₃ alkyl;-   R₃ is selected from H and C₁₋₃ alkyl;-   or R₂ and R₃ together with the nitrogen atoms to which they are    attached and the carbon atom connecting the two nitrogen atoms form    a 5- or 6-membered ring;-   R₄ is selected from H and C₁₋₃ alkyl;-   R₅ is selected from H and C₁₋₆ alkyl;-   R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the    C₁₋₆ alkyl is optionally substituted with one or more substituents    selected from the group consisting of halogen, OR^(a), SR^(a),    —C(O)OR^(a), and —SC(NH)NH₂;-   R₇ is selected from H and C₁₋₆ alkyl;-   or R₆ and R₇ together with the carbon and nitrogen atoms to which    they are attached form a ring having one of the formulas:

-   wherein the ring is optionally substituted on a carbon atom with    C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with    one or more OH;-   or R₅ and R₇ together with the carbon atoms to which they are    attached and the nitrogen atom connecting the two carbon atoms form    a ring having one of the formulas:

-   R₈ is selected from H and halogen;-   R₁₂ is selected from H, halogen, and C₁₋₆ alkyl;-   R₁₃ is selected from H, halogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂,    wherein C₁₋₆ alkyl is optionally substituted with one or more of    OR^(c) and aryl;-   R₁₄ is selected from H and aryl;-   or R₁₃ and R₁₄ together with the carbon atoms to which they are    attached form a 5- or 6-membered cycloalkyl ring;-   R₁₅ is selected from H, C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is    optionally substituted with one or more R^(b).-   each R^(a) is independently selected from H and C₁₋₆ alkyl;-   each R^(b) is independently selected from C₂₋₆ alkenyl, OR^(c),    N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl;-   each R^(c) is independently selected from hydrogen, C₁₋₆ alkyl,    aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are each    optionally substituted with one or more R^(d); and-   each R^(d) is independently selected from OH, O(C₁₋₃ alkyl), NH₂,    NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

In some embodiments provided herein is a pharmaceutical compositioncomprising a compound of Formula (AA), Formula (A), Formula (I), Formula(II), or Formula (III), or a tautomer thereof or a pharmaceuticallyacceptable salt of the compound or tautomer, and a pharmaceuticallyacceptable carrier.

In some embodiments provided herein is a method of treating a microbialinfection comprising administering to a subject in need thereof aneffective amount of a compound of Formula (AA), Formula (A), Formula(I), Formula (II), or Formula (III), or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer, or apharmaceutically acceptable composition as provided herein.

In some embodiments provided herein is a method of preventing amicrobial infection comprising administering to a subject in needthereof an effective amount of a compound of Formula (AA), Formula (A),Formula (I), Formula (II), or Formula (III), or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer, or apharmaceutically acceptable composition as provided herein.

In some embodiments provided herein is a method of reducing the risk ofa microbial infection comprising administering to a subject in needthereof an effective amount of a compound of Formula (AA), Formula (A),Formula (I), Formula (II), or Formula (III), or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer, or apharmaceutically acceptable composition as provided herein.

In some embodiments provided herein is a method of delaying the onset ofa microbial infection comprising administering to a subject in needthereof an effective amount of a compound of Formula (AA), Formula (A),Formula (I), Formula (II), or Formula (III), or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer, or apharmaceutically acceptable composition as provided herein.

In some embodiments provided herein is a method of treating a microbialinfection comprising administering to a subject in need thereof aneffective amount of a compound of Formula (AA), Formula (A), Formula(I), Formula (II), or Formula (III), or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer, or apharmaceutically acceptable composition as provided herein.

In some embodiments provided herein is a use of a compound of Formula(AA), Formula (A), Formula (I), Formula (II), or Formula (III), or atautomer thereof or a pharmaceutically acceptable salt of the compoundor tautomer, in the manufacture of a medicament for treating,preventing, or reducing a microbial infection in a subject.

In some embodiments provided herein is a compound of Formula (AA),Formula (A), Formula (I), Formula (II), or Formula (III), or a tautomerthereof or a pharmaceutically acceptable salt of the compound ortautomer, for use in treating, preventing, or reducing a microbialinfection in a subject.

In addition, the disclosure provides methods of synthesizing theforegoing compounds and tautomers thereof, and pharmaceuticallyacceptable salts of the compounds and tautomers. Following synthesis, aneffective amount of one or more of the compounds or tautomers thereof,or pharmaceutically acceptable salts of the compounds or tautomers canbe formulated with a pharmaceutically acceptable carrier foradministration to a human or animal for use as antimicrobial agents,particularly as antibacterial agents. In certain embodiments, thecompounds of the present disclosure are useful for treating, preventing,reducing the risk of, or delaying the onset of microbial infections orfor the manufacture of a medicament for treating, preventing, reducingthe risk of, or delaying the onset of microbial infections.

Accordingly, the compounds or tautomers thereof, or pharmaceuticallyacceptable salts of the compounds or tautomers or their formulations canbe administered, for example, via oral, parenteral, intravenous, otic,ophthalmic, nasal, or topical routes, to provide an effective amount ofthe compound or tautomer thereof, or pharmaceutically acceptable salt ofthe compound or tautomer to the human or animal.

The foregoing and other aspects and embodiments of the disclosure can bemore fully understood by reference to the following detailed descriptionand claims.

DETAILED DESCRIPTION

The present disclosure utilizes a structure based drug design approachfor discovering and developing new antimicrobial agents. This approachstarts with a high resolution X-ray crystal of a ribosome to design newclasses of antimicrobial compounds having specific chemical structures,ribosome binding characteristics, and antimicrobial activity. Thisstructure based drug discovery approach is described in the followingpublication: Franceschi, F. and Duffy, E. M., “Structure-based drugdesign meets the ribosome”, Biochemical Pharmacology, vol. 71, pp.1016-1025 (2006).

Based on this structure based drug design approach, the presentdisclosure describes new chemical classes of antimicrobial compoundsuseful for treating bacterial infections in humans and animals. Withoutbeing limited by theories, these compounds are believed to inhibitbacterial ribosome function by binding to the ribosome. By takingadvantage of these ribosome binding sites, the antimicrobial compoundsof the present disclosure can provide better activity, especiallyagainst resistant strains of bacteria, than currently availableantibiotic compounds.

The present disclosure therefore fills an important ongoing need for newantimicrobial agents, particularly for antimicrobial agents, havingactivity against resistant pathogenic bacterial organisms.

The present disclosure provides a family of compounds or tautomersthereof, that can be used as antimicrobial agents, more particularly asantibacterial agents.

The present disclosure also includes pharmaceutically acceptable saltsof the compounds and tautomers.

The compounds or tautomers thereof, or pharmaceutically acceptable saltsof the compounds or tautomers disclosed herein can have asymmetriccenters. Compounds or tautomers thereof, or pharmaceutically acceptablesalts of the compounds or tautomers of the present disclosure containingan asymmetrically substituted atom can be isolated in optically activeor racemic forms. Optically active forms of compounds can be prepared,for example, by resolution of racemic forms or by synthesis fromoptically active starting materials. Many geometric isomers of olefins,C═N double bonds, and the like can also be present in the compounds ortautomers thereof, or pharmaceutically acceptable salts of the compoundsor tautomers disclosed herein, and all such stable isomers arecontemplated in the present disclosure. Cis and trans geometric isomersof the compounds or tautomers thereof, or pharmaceutically acceptablesalts of the compounds or tautomers of the present disclosure aredescribed and can be isolated as a mixture of isomers or as separateisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a structure are intended, unless specificstereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds or tautomers thereof, orpharmaceutically acceptable salts of the compounds or tautomers of thepresent disclosure and intermediates made herein are considered to bepart of the present disclosure. All tautomers of shown or describedcompounds are also considered to be part of the present disclosure.Furthermore, the disclosure also includes metabolites of the compoundsdisclosed herein.

The disclosure also provides for isotopically-labeled compounds ortautomers thereof, or pharmaceutically acceptable salts of the compoundsor tautomers, which are identical to those recited in formulae of thedisclosure, but for the replacement of one or more atoms by an atomhaving an atomic mass or mass number different from the atomic mass ormass number most commonly found in nature. Examples of isotopes that canbe incorporated into compounds or tautomers thereof, or pharmaceuticallyacceptable salts of the compounds or tautomers of the disclosure includeisotopes of hydrogen, carbon, nitrogen, and fluorine, such as ³H, ¹¹C,¹⁴C, and ¹⁸F.

The compounds of the present disclosure or tautomers thereof, orpharmaceutically acceptable salts of the compounds or tautomers thatcontain the aforementioned isotopes and/or isotopes of other atoms arewithin the scope of the present disclosure. Isotopically-labeledcompounds or tautomers thereof, or pharmaceutically acceptable salts ofthe compounds or tautomers of the present disclosure, for example, thoseinto which radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. Tritium,i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferreddue to their ease of preparation and detectability. ¹¹C and ¹⁸F isotopesare particularly useful in PET (positron emission tomography). PET isuseful in brain imaging. Further, substitution with heavier isotopessuch as deuterium, i.e., ²H, can afford certain therapeutic advantagesresulting from greater metabolic stability, i.e., increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labeled compounds or tautomers thereof,or pharmaceutically acceptable salts of the compounds or tautomershaving a formula of the disclosed herein can generally be prepared asdescribed in the procedures, Schemes and/or in the Examples disclosedherein, by substituting a non-isotopically labeled reagent with areadily available isotopically labeled reagent. In one embodiment, thecompounds or tautomers thereof, or pharmaceutically acceptable salts ofthe compounds or tautomers disclosed herein are not isotopicallylabeled.

When any variable (e.g., R) occurs more than one time in any constituentor formulae of the disclosed herein, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more Rmoieties, then R at each occurrence is selected independently from thedefinition of R. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compoundswithin a designated atom's normal valence.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent can be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent can be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

In cases wherein compounds of the present disclosure, or tautomersthereof, or pharmaceutically acceptable salts of the compounds ortautomers thereof, contain nitrogen atoms, these, where appropriate, canbe converted to N-oxides by treatment with an oxidizing agent (e.g.,meta-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides). Thus,shown and claimed nitrogen atoms are considered to cover both the shownnitrogen and its N-oxide (N→O) derivative, as appropriate. In someembodiments, the present disclosure relates to N-oxides of the compoundsor tautomers thereof, or pharmaceutically acceptable salts of thecompounds or tautomers disclosed herein.

One approach to developing improved anti-proliferative andanti-infective agents is to provide modulators (for example, inhibitors)of ribosome function.

Ribosomes are ribonucleoproteins, which are present in both prokaryotesand eukaryotes. Ribosomes are the cellular organelles responsible forprotein synthesis. During gene expression, ribosomes translate thegenetic information encoded in a messenger RNA into protein (Garrett etal. (2000) “The Ribosome: Structure, Function, Antibiotics and CellularInteractions,” American Society for Microbiology, Washington, D.C.).

Ribosomes comprise two nonequivalent ribonucleoprotein subunits. Thelarger subunit (also known as the “large ribosomal subunit”) is abouttwice the size of the smaller subunit (also known as the “smallribosomal subunit”). The small ribosomal subunit binds messenger RNA(mRNA) and mediates the interactions between mRNA and transfer RNA(tRNA) anticodons on which the fidelity of translation depends. Thelarge ribosomal subunit catalyzes peptide bond formation, i.e., thepeptidyl-transferase reaction of protein synthesis, and includes, atleast, three different tRNA binding sites known as the aminoacyl,peptidyl, and exit sites. The aminoacyl site or A-site accommodates theincoming aminoacyl-tRNA that is to contribute its amino acid to thegrowing peptide chain. Also, the A space of the A-site is important. Thepeptidyl site or P-site accommodates the peptidyl-tRNA complex, i.e.,the tRNA with its amino acid that is part of the growing peptide chain.The exit or E-site accommodates the deacylated tRNA after it has donatedits amino acid to the growing polypeptide chain.

1. DEFINITIONS

“Isomerism” means compounds that have identical molecular formulae butthat differ in the nature or the sequence of bonding of their atoms orin the arrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

“Chiral isomer” means a compound with at least one chiral center. Acompound with one chiral center has two enantiomeric forms of oppositechirality and may exist either as an individual enantiomer or as amixture of enantiomers. A mixture containing equal amounts of individualenantiomeric forms of opposite chirality is termed a “racemic mixture”.A compound that has more than one chiral center has 2^(n-1) enantiomericpairs, where n is the number of chiral centers. Compounds with more thanone chiral center may exist as either an individual diastereomer or as amixture of diastereomers, termed a “diastereomeric mixture”. When onechiral center is present, a stereoisomer may be characterized by theabsolute configuration (R or S) of that chiral center. Absoluteconfiguration refers to the arrangement in space of the substituentsattached to the chiral center. The substituents attached to the chiralcenter under consideration are ranked in accordance with the SequenceRule of Cahn, Ingold and Prelog. (Cahn et al, Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahnand Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia1956, 12, 81; Cahn, J., Chem. Educ. 1964, 41, 116).

“Geometric Isomers” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Further, the compounds discussed in this application include all atropicisomers thereof. “Atropic isomers” are a type of stereoisomer in whichthe atoms of two isomers are arranged differently in space. Atropicisomers owe their existence to a restricted rotation caused by hindranceof rotation of large groups about a central bond. Such atropic isomerstypically exist as a mixture, however, as a result of recent advances inchromatography techniques, it has been possible to separate mixtures oftwo atropic isomers in select cases.

Some compounds of the present disclosure can exist in a tautomeric formwhich is also intended to be encompassed within the scope of the presentdisclosure. “Tautomers” refers to compounds whose structures differmarkedly in the arrangement of atoms, but which exist in easy and rapidequilibrium. It is to be understood that compounds of the presentdisclosure may be depicted as different tautomers. It should also beunderstood that when compounds have tautomeric forms, all tautomericforms are intended to be within the scope of the disclosure, and thenaming of the compounds does not exclude any tautomeric form.

The compounds and pharmaceutically acceptable salts of the presentdisclosure can exist in one or more tautomeric forms, including the enoland imine form and the keto and enamine form, and geometric isomers andmixtures thereof. All such tautomeric forms are included within thescope of the present disclosure. Tautomers exist as mixtures of atautomeric set in solution. In solid form, usually one tautomerpredominates. Even though one tautomer may be described, the presentdisclosure includes all tautomers of the compounds disclosed herein.

A tautomer is one of two or more structural isomers that exist inequilibrium and are readily converted from one isomeric form to another.This reaction results in the formal migration of a hydrogen atomaccompanied by a shift of adjacent conjugated double bonds. In solutionswhere tautomerization is possible, a chemical equilibrium of thetautomers can be reached. The exact ratio of the tautomers depends onseveral factors, including temperature, solvent, and pH. The concept oftautomers that are interconvertible by tautomerizations is calledtautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism, a simultaneous shift of electronsand a hydrogen atom occurs. Ring-chain tautomerism, exhibited by glucoseand other sugars, arises as a result of the aldehyde group (—CHO) in asugar chain molecule reacting with one of the hydroxy groups (—OH) inthe same molecule to give it a cyclic (ring-shaped) form.

Tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formationof a delocalized anion (e.g., an enolate); 3. protonation at a differentposition of the anion; Acid: 1. protonation; 2. formation of adelocalized cation; 3. deprotonation at a different position adjacent tothe cation.

Common tautomeric pairs include: ketone—enol, amide—nitrile,lactam—lactim, amide—imidic acid tautomerism in heterocyclic rings(e.g., in the nucleobases guanine, thymine, and cytosine), amine—enamineand enamine—enamine. Examples below are included for illustrativepurposes, and the present disclosure is not limited to the examples:

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom, usually a carbon, oxygen, or nitrogenatom, is replaced with a selection from the indicated group, providedthat the designated atom's normal valency is not exceeded, and that thesubstitution results in a stable compound. When a substituent is keto oroxo (i.e., ═O), then 2 hydrogens on the atom are replaced. Ring doublebonds, as used herein, are double bonds that are formed between twoadjacent ring atoms (e.g., C═C, C═N, N═N, etc.).

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁₋₄ is intended toinclude C₁, C₂, C₃, and C₄. C₁₋₆ alkyl is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkyl groups and C₁₋₈ is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, and C₈. Some examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, and n-octyl.

As used herein, “alkenyl” is intended to include hydrocarbon chains ofeither straight or branched configuration and one or more unsaturatedcarbon-carbon bonds that can occur in any stable point along the chain,such as ethenyl and propenyl. For example, C₂₋₆ alkenyl is intended toinclude C₂, C₃, C₄, C₅, and C₆ alkenyl groups and C₂₋₈ alkenyl isintended to include C₂, C₃, C₄, C₅, C₆, C₇, and C₈.

As used herein, “alkylene” is intended to include moieties which arediradicals, i.e., having two points of attachment. A non-limitingexample of such alkylene moiety that is a diradical is —CH₂CH₂—, i.e., aC₂ alkyl group that is covalently bonded via each terminal carbon atomto the remainder of the molecule. The alkylene diradicals are also knownas “alkylenyl” radicals. Alkylene groups can be saturated or unsaturated(e.g., containing —CH═CH— or —C≡C— subunits), at one or severalpositions. In some embodiments, alkylene groups include 1 to 9 carbonatoms (for example, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2carbon atoms). Some examples of alkylene groups include, but not limitedto, methylene, ethylene, n-propylene, iso-propylene, n-butylene,iso-butylene, sec-butylene, tert-butylene, n-pentylene, iso-pentylene,sec-pentylene and neo-pentylene.

As used herein, “cycloalkyl” is intended to include saturated orunsaturated nonaromatic ring groups, such as cyclopropyl, cyclobutyl, orcyclopentyl. C₃₋₈ cycloalkyl is intended to include C₃, C₄, C₅, C₆, C₇,and C₈ cycloalkyl groups. Cycloalkyls may include multiple spiro- orfused rings.

As used herein, the term “heterocycloalkyl” refers to a saturated orunsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic(fused, bridged, or spiro rings), or 11-14 membered tricyclic ringsystem (fused, bridged, or spiro rings) having one or more heteroatoms(such as O, N, S, or Se), unless specified otherwise. A heterocycloalkylgroup containing a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6membered heterocycloalkyl having 1 or 2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur and having one or moreoxidized ring members. In some embodiments, the heterocycloalkyl is amonocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or4 heteroatoms independently selected from nitrogen, oxygen, or sulfurand having one or more oxidized ring members. Examples ofheterocycloalkyl groups include, but are not limited to, piperidinyl,piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl,indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxetanyl,thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl,dihydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl,2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl,1,4-dioxa-8-azaspiro[4.5]decanyl and the like.

As used herein, “amine” or “amino” refers to unsubstituted —NH₂ unlessotherwise specified.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo substituents.

As used herein, “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with one or more halogen(for example —C_(v)F_(w)H_(2v−w+1) wherein v=1 to 3 and w=1 to (2v+1)).Examples of haloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The term “haloalkoxy” as used herein refers to an alkoxy group, asdefined herein, which is substituted one or more halogen. Examples ofhaloalkoxy groups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

As used herein, “alkoxyl” or “alkoxy” refers to an alkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge. C₁₋₆ alkoxy, is intended to include C₁, C₂, C₃, C₄,C₅, and C₆ alkoxy groups. C₁₋₈ alkoxy, is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, and C₈ alkoxy groups. Examples of alkoxy include,but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.

As used herein, “aryl” includes groups with aromaticity, including“conjugated,” or multicyclic systems with at least one aromatic ring anddo not contain any heteroatom in the ring structure. Aryl may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“Cn-m aryl” refers to an aryl group having from n to m ring carbonatoms. In some embodiments, aryl groups have from 6 to 10 carbon atoms.In some embodiments, the aryl group is phenyl or naphthyl.

As used herein, the term “aromatic heterocycle”, “aromatic heterocyclic”or “heteroaryl” ring is intended to mean a stable 5, 6, 7, 8, 9, 10, 11,or 12-membered monocyclic or bicyclic aromatic ring which consists ofcarbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen,and sulfur. In the case of bicyclic aromatic heterocyclic or heterocycleor heteroaryl rings, only one of the two rings needs to be aromatic(e.g., 2,3-dihydroindole), though both can be (e.g., quinoline). Thesecond ring can also be fused or bridged as defined above forheterocycles. The nitrogen atom can be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, as defined). Thenitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→Oand S(O)_(p), wherein p=1 or 2). In certain compounds, the total numberof S and O atoms in the aromatic heterocycle is not more than 1.

Examples of aromatic heterocycles, aromatic heterocyclics or heteroarylsinclude, but are not limited to, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, benzooxadiazoly,carbazolyl, 4aH-carbazolyl, carbolinyl, cinnolinyl, furazanyl,imidazolyl, imidazolonyl, 1H-indazolyl, indolizinyl, indolyl,3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, methylbenztriazolyl,methylfuranyl, methylimidazolyl, methylthiazolyl, naphthyridinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazolyl,pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridinonyl, pyridyl,pyrimidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, tetrahydroquinolinyl, tetrazolyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, and 1,3,4-triazolyl. The term “hydroxyalkyl” means analkyl group as defined above, where the alkyl group is substituted withone or more OH groups. Examples of hydroxyalkyl groups include HO—CH₂—,HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond, i.e., C≡∂N.

As used herein, “oxo” is means a “═O” group.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds or tautomers thereof, or salts thereof, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds or tautomers thereof, wherein the parentcompound or a tautomer thereof, is modified by making of the acid orbase salts thereof of the parent compound or a tautomer thereof.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound, or a tautomer thereof, formed, for example, fromnon-toxic inorganic or organic acids. For example, such conventionalnon-toxic salts include, but are not limited to, those derived frominorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present disclosure can besynthesized from the parent compound or a tautomer thereof, thatcontains a basic or acidic moiety by conventional chemical methods.Generally, such pharmaceutically acceptable salts can be prepared byreacting the free acid or base forms of these compounds or tautomersthereof with a stoichiometric amount of the appropriate base or acid inwater or in an organic solvent, or in a mixture of the two; generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company,Easton, Pa., USA, p. 1445 (1990).

As used herein, “stable compound” and “stable structure” are meant toindicate a compound that is sufficiently robust to survive isolation toa useful degree of purity from a reaction mixture, and formulation intoan efficacious therapeutic agent.

As used herein, the term “treating” means to provide a therapeuticintervention to cure or ameliorate an infection. In some embodiments,“treating” refers to administering a compound or pharmaceuticalcomposition as provided herein for therapeutic purposes. The term“therapeutic treatment” refers to administering treatment to a patientalready suffering from a disease thus causing a therapeuticallybeneficial effect, such as ameliorating existing symptoms, amelioratingthe underlying metabolic causes of symptoms, postponing or preventingthe further development of a disorder, and/or reducing the severity ofsymptoms that will or are expected to develop.

As used herein, the term “preventing”, as used herein means, tocompletely or almost completely stop an infection from occurring, forexample when the patient or subject is predisposed to an infection or atrisk of contracting an infection. Preventing can also includeinhibiting, i.e., arresting the development, of an infection.

As used herein, the term “reducing the risk of”, as used herein, meansto lower the likelihood or probability of an infection occurring, forexample when the patient or subject is predisposed to an infection or atrisk of contracting an infection.

As used herein, “unsaturated” refers to compounds having at least onedegree of unsaturation (e.g., at least one multiple bond) and includespartially and fully unsaturated compounds.

As used herein, the term “effective amount” or “therapeuticallyeffective amount” refers to an amount of a compound or a tautomerthereof, or a pharmaceutically acceptable salt of the compound ortautomer (including combinations of compounds and/or tautomers thereof,and/or pharmaceutically acceptable salts of the compound or tautomer) ofthe present disclosure that is sufficient to elicit biological activitywhen administered alone or in combination as an antimicrobial agent. Forexample, an effective amount refers to an amount of the compound ortautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer that is present in a composition, a formulation or on amedical device given to a recipient patient or subject sufficient toelicit biological activity, for example, anti-infective activity, suchas e.g., anti-microbial activity, anti-bacterial activity, anti-fungalactivity, anti-viral activity, or anti-parasitic activity.

The term “prophylactically effective amount” means an amount of acompound or a tautomer of the compound, or a pharmaceutically acceptablesalt of the compound or tautomer (including combinations of compoundsand/or tautomers thereof, and/or pharmaceutically acceptable saltsthereof), of the present disclosure that is sufficient to prevent orreduce the risk of an infection when administered alone or incombination as an antimicrobial agent. For example, a prophylacticallyeffective amount refers to an amount of the compound or tautomerthereof, or a pharmaceutically acceptable salt of the compound ortautomer that is present in a composition, a formulation, or on amedical device given to a recipient patient or subject sufficient toprevent or reduce the risk of an infection due to a surgical procedureor an invasive medical procedure.

As used herein, the terms “expose,” “exposure,” or “exposed” means thata subject comes in contact in any way with a bacterium or any componentthereof (e.g., bacterial cell wall, bacterial cell membrane, a bacterialnucleic acid, a bacterial polynucleotide, a bacterial protein, abacterial polypeptide, a bacterial spore, and a bacterial toxin). Forexample, a subject can be exposed to a bacterium or any componentthereof by ingesting, inhaling, or touching anything which contains thebacterium or any component thereof. Bacterium, as well as components ofa bacterium (e.g., bacterial cell wall, bacterial cell membrane, abacterial nucleic acid, a bacterial polynucleotide, a bacterial protein,a bacterial polypeptide, a bacterial spore, and a bacterial toxin), cancause an infection or symptoms of an infection in a subject. An exampleof a bacterial component that can cause an infection is a bacterialspore.

“Suspected exposure,” as used herein, means that there is certainpossibility, although it is not known, that a subject has been exposedto a microorganism, for example, a bacterium, and thus is at the risk ofa microbial (bacterial) infection, such as a bacterial infection. Insome embodiments, “suspected exposure” means that there is greater thana 50% possibility that a subject has been exposed to a microorganism,for example, a bacterium.

As used herein, a “symptom” of a microbial infection, for example, abacterial infection, can be any indication that the subject exposed orsuspected of being exposed to the bacterium is not normal, well, orcomfortable, regardless of the subject's subjective perception orfeeling. “Symptom” includes, but is not limited to, headache,stomachache, abdominal cramps, abdominal pain, muscle pain, fever,diarrhea, vomiting, coughing, weakness, tiredness, soreness, rash orbumps on skin, wounds in any parts of the body (skin, head, eye, ear,nose, mouth, torso, limbs, arm, hand, leg, foot, etc.), and anabnormality in any tissue or organ (skin, bone, blood, lymph, intestine,stomach, pancreas, brain, heart, lung, liver, spleen, kidney, bladder,ovary, etc.).

A bacterium is “easily produced or disseminated” if the bacterium can beproduced or disseminated by routine methods, processes, or techniquesand with common materials, reagents, and equipment available in the art,or by methods, processes, or techniques and with materials, reagents,and equipment which are accessible to and can be operated or used by alay person having little or no training in the art.

The term “moderate morbidity” refers to morbidity of no less than 10%,no less than 15%, no less than 20%, no less than 25%, no less than 30%,no less than 35%, no less than 40%, or no less than 45%. The term “highmorbidity” refers to morbidity of no less than 50%, no less than 55%, noless than 60%, no less than 65%, no less than 70%, no less than 75%, noless than 80%, no less than 85%, no less than 90%, or no less than 95%.

The term “moderate mortality” refers to mortality of no less than 10%,no less than 15%, no less than 20%, no less than 25%, no less than 30%,no less than 35%, no less than 40%, or no less than 45%. The term “highmortality” refers to mortality of no less than 50%, no less than 55%, noless than 60%, no less than 65%, no less than 70%, no less than 75%, noless than 80%, no less than 85%, no less than 90%, or no less than 95%.

The terms “resistance” or “resistant” refer to the antibiotic/organismstandards as defined by the Clinical and Laboratories StandardsInstitute (CLSI) and/or the Food and Drug Administration (FDA).

As used herewith, the terms “multi-drug resistance,” “multi-drugresistant,” or “MDR” refer to acquired non-susceptibility to at leasttwo antimicrobial agents, e.g., resistance to one agent in three or moreantimicrobial categories. The terms “extremely-drug resistant,”“extensive drug resistance,” or “XDR,” as used herein, refer to acquirednon-susceptibility to at least one agent in all but two or fewerantimicrobial categories. For example, bacterial isolates remainsusceptible to only one or two categories. Accordingly, an XDR bacterialisolate is always an MDR bacterial isolate, but an MDR bacterial isolateis not necessarily an XDR bacterial isolate. For example, an XDRmicroorganism is a Pseudomonas aeruginosa isolate that is susceptible toonly one or two antimicrobial categories, such as a Pseudomonasaeruginosa isolate that is only susceptible to polymyxins (for example,colistin) or only susceptible to a pyrrolocytosine compound describedherein. See, for example, Magiorakos et al., Clin. Microbial Infect.2012; 18: 268-281, the content of which is hereby incorporated byreference in its entirety.

The term “subject” includes animals which either have or are susceptibleor are suspected to have acquired a microbial infection (e.g., abacterial infection). Examples of subjects include animals such as farmanimals (e.g., cows, pigs, horses, goats, rabbits, sheep, chickens,etc.), lab animals (mice, rats, monkeys, chimpanzees, etc.), pets (e.g.,dogs, cats, ferrets, hamsters, etc.), birds (e.g., chickens, turkeys,ducks, geese, crows, ravens, sparrows, etc.), primates (e.g., monkeys,gorillas, chimpanzees, bonobos, and humans), and other animals (e.g.,squirrels, raccoons, mice, rats, etc.). In some embodiments, the subjectis a mouse or rat. In yet another embodiment, the subject is a cow, apig, or a chicken. In another embodiment, the subject is a human.

As used herein, the term ESBL is extended spectrum beta-lactamase. Theterm KPC is Klebsiella pneumoniae carbapenemase.

As used herein, the term acute bacterial skin and skin structureinfection (ABSSSI) encompasses complicated skin and skin structureinfections (cSSSI) and complication skin and soft tissue infections(cSSTI), which have been used interchangeably. The terms uncomplicatedskin and skin structure infections (uCSSSI) and uncomplicated skin andsoft tissue infections (uCSSTI) have been used interchangeably.

As used herein, the term “spp.” is the abbreviation for species.

As used herein, the term “formulae of the disclosure” or “formulaedisclosed herein” includes one or more of the Formulae: (AA), (A), (I),(II), and (III).

As used herein, the term “compound of the disclosure” or “compounddisclosed herein” includes one or more compounds of the formulae of thedisclosure or a compound explicitly disclosed herein.

The term “about,” when used in conjunction with a numerical range,modifies that range by extending the boundaries above and below thenumerical values set forth. In general, the term “about” is used hereinto modify a numerical value above and below the stated value by avariance of 10%. Thus, “about 10” means 9 to 11.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present disclosure also consistessentially of, or consist of, the recited components, and that theprocesses of the present disclosure also consist essentially of, orconsist of, the recited processing steps. Further, it should beunderstood that the order of steps or order for performing certainactions are immaterial so long as the invention remains operable.Moreover, two or more steps or actions can be conducted simultaneously.

2. COMPOUNDS OF THE DISCLOSURE

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

J is selected from

X is selected from a 5- or 6-membered heterocyclyl ring and phenyl,wherein each of the 5- or 6-membered heterocyclyl ring and the phenyl isoptionally substituted with one or more R^(X);

Z is selected from

R₁ is selected from H, C₁₋₃ alkyl, and C₂₋₄ alkenyl;

R₂ is selected from H and C₁₋₃ alkyl;

R₃ is selected from H and C₁₋₃ alkyl;

or R₂ and R₃ together with the nitrogen atoms to which they are attachedand the carbon atom connecting the two nitrogen atoms form a 5- or6-membered ring;

or R₁ and R₃ together with the nitrogen and sulfur atom to which theyare attached and the carbon atom connecting the two nitrogen atoms forma 5- or 6-membered ring;

R₄ is selected from H and C₁₋₃ alkyl;

R₅ is selected from H and C₁₋₆ alkyl;

R₆ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₃₋₆ cycloalkyl,wherein the C₁₋₆ alkyl is optionally substituted with one or moresubstituents selected from the group consisting of halogen, OR^(a),SR^(a), —C(O)OR^(a), —SC(NH)NH₂, C₃₋₆ cycloalkyl, and 3-6 memberedheterocyclyl;

R₇ is selected from H and C₁₋₆ alkyl;

or R₆ and R₇ together with the carbon and nitrogen atoms to which theyare attached form a ring having one of the formulas

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH;

or R₅ and R₇ together with the carbon atoms to which they are attachedand the nitrogen atom connecting the two carbon atoms form a ring havingone of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withOH;

Q is selected from C₁₋₂ alkylene or —C(O)—;

R₂₁ is selected from H, C₁₋₆ alkyl optionally substituted with 1-3 halo;

R₈ is selected from H and halogen;

each R^(X) is independently selected from halogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆ cycloalkyl,and aryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore R^(b);

or two adjacent R_(X) come together with the atoms to which they areattached to form a 5- or 6-membered ring;

each R^(b) is independently selected from C₂₋₆ alkenyl, OR^(c),N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, OC(NH)NH₂, and aryl;

each R^(c) is independently selected from H, C₁₋₆ alkyl, aryl,—C(O)aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are eachoptionally substituted with one or more R^(d); and

each R^(d) is independently selected from C₁₋₃ alkyl, OH, O(C₁₋₃ alkyl),NO₂, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

In some embodiments of Formula (AA), J is

In some embodiments of Formula (AA), X is phenyl optionally substitutedwith one or more R^(X). For example, X is phenyl substituted with one ormore halogens. In some embodiments, X is phenyl substituted with twohalogens. For example, X is phenyl substituted with fluoro and chloro.

In some embodiments of Formula (AA), Z is

In some embodiments of Formula (AA), R₁ is selected from H, C₁₋₃ alkyl,and C₂₋₄ alkenyl; R₂ is selected from H and C₁₋₃ alkyl; R₃ is selectedfrom H and C₁₋₃ alkyl; or R₁ and R₃ together with the nitrogen andsulfur atom to which they are attached and the carbon atom connectingthe two nitrogen atoms form a 5- or 6-membered ring.

In some embodiments of Formula (AA), R₄ is H.

In some embodiments of Formula (AA), R₅ is H.

In some embodiments of Formula (AA), R₆ and R₇ together with the carbonand nitrogen atoms to which they are attached form a ring having theformula:

In some embodiments of Formula (AA), R₈ is selected from H and halogen.For example, R₈ is H.

In some embodiments of Formula (AA), each R^(X) is independentlyselected from halogen, C₁₋₆ alkyl, and C₁₋₄ haloalkyl. For example, eachR^(X) is halogen (e.g., fluoro or chloro).

In some embodiments of Formula (AA), J is

X is phenyl substituted with one or more halogens (e.g., X is phenylsubstituted with fluoro and chloro); Z is

R₁ is selected from C₁₋₃ alkyl and C₂₋₄ alkenyl; R₂ is H; R₃ is selectedfrom H and C₁₋₃ alkyl; or R₁ and R₃ together with the nitrogen andsulfur atom to which they are attached and the carbon atom connectingthe two nitrogen atoms form a 5- or 6-membered ring; R₄ is H; R₅ is H;R₆ and R₇ together with the carbon and nitrogen atoms to which they areattached form a ring having the formula:

and R₈ is selected from H and halogen (e.g., R₈ is H).

In some embodiments, the present application provides a compound ofFormula (A):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

X is selected from a 5- or 6-membered heterocyclyl ring and phenyl,wherein each of the 5- or 6-membered heterocyclyl ring and the phenyl isoptionally substituted with one or more R^(X);

Z is selected from

R₁ is selected from H and C₁₋₃ alkyl;

R₂ is selected from H and C₁₋₃ alkyl;

R₃ is selected from H and C₁₋₃ alkyl;

or R₂ and R₃ together with the nitrogen atoms to which they are attachedand the carbon atom connecting the two nitrogen atoms form a 5- or6-membered ring;

R₄ is selected from H and C₁₋₃ alkyl;

R₅ is selected from H and C₁₋₆ alkyl;

R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl is optionally substituted with one or more substituents selectedfrom the group consisting of halogen, OR^(a), SR^(a), —C(O)OR^(a),—SC(NH)NH₂, C₃₋₆ cycloalkyl, and 3-6 membered heterocyclyl;

R₇ is selected from H and C₁₋₆ alkyl;

or R₆ and R₇ together with the carbon and nitrogen atoms to which theyare attached form a ring having one of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH;

or R₅ and R₇ together with the carbon atoms to which they are attachedand the nitrogen atom connecting the two carbon atoms form a ring havingone of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withOH;

Q is selected from C₁₋₂ alkylene or —C(O)—;

R₂₁ is selected from H, C₁₋₆ alkyl optionally substituted with 1-3 halo;

R₈ is selected from H and halogen;

each R^(X) is independently selected from halogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆ cycloalkyl,and aryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore R^(b);

or two adjacent R^(X) come together with the atoms to which they areattached to form a 5- or 6-membered ring;

each R^(a) is independently selected from H and C₁₋₆ alkyl;

each R^(b) is independently selected from C₂₋₆ alkenyl, OR^(c),N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl;

each R^(c) is independently selected from H, C₁₋₆ alkyl, aryl,—C(O)aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are eachoptionally substituted with one or more R^(d); and

each R^(d) is independently selected from C₁₋₃ alkyl, OH, O(C₁₋₃ alkyl),NO₂, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

In some embodiments, the present application provides a compound ofFormula (I).

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   X is selected from a 5- or 6-membered heterocyclyl ring and phenyl,    wherein each of the 5- or 6-membered heterocyclyl ring and phenyl is    optionally substituted with one or more R^(X);-   R₁ is selected from H and C₁₋₃ alkyl;-   R₂ is selected from H and C₁₋₃ alkyl;-   R₃ is selected from H and C₁₋₃ alkyl;-   or R₂ and R₃ together with the nitrogen atoms to which they are    attached and the carbon atom connecting the two nitrogen atoms form    a 5- or 6-membered ring;-   R₄ is selected from H and C₁₋₃ alkyl;-   R₅ is selected from H and C₁₋₆ alkyl;-   R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the    C₁₋₆ alkyl is optionally substituted with one or more substituents    selected from the group consisting of halogen, OR^(a), SR^(a),    —C(O)OR^(a), —SC(NH)NH₂, C₃₋₆ cycloalkyl, and 3-6 membered    heterocyclyl;-   R₇ is selected from H and C₁₋₆ alkyl;-   or R₆ and R₇ together with the carbon and nitrogen atoms to which    they are attached form a ring having one of the formulas:

-   wherein the ring is optionally substituted on a ring carbon atom    with C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted    with one or more OH;-   or R₅ and R₇ together with the carbon atoms to which they are    attached and the nitrogen atom connecting the two carbon atoms form    a ring having one of the formulas:

-   R₈ is selected from H and halogen;-   each R^(X) is independently selected from halogen, C₁₋₆ alkyl, C₁₋₄    haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆    cycloalkyl, and aryl, wherein the C₁₋₆ alkyl is optionally    substituted with one or more R^(b);-   or two adjacent R^(X) come together with the atoms to which they are    attached to form a 5- or 6-membered ring;-   each R^(a) is independently selected from H and C₁₋₆ alkyl;-   each R^(b) is independently selected from C₂₋₆ alkenyl, OR^(c),    N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl;-   each R^(c) is independently selected from H, C₁₋₆ alkyl, aryl,    —C(O)aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are    each optionally substituted with one or more R^(d); and-   each R^(d) is independently selected from C₁₋₃ alkyl, OH, O(C₁₋₃    alkyl), NO₂, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

In some embodiments of Formula (I), each of R₁, R₂, and R₃ is H. In someembodiments, two of R₁, R₂, and R₃ are H, and the other is C₁₋₃ alkyl.For example, two of R₁, R₂, and R₃ are H, and the other is methyl. Insome embodiments, one of R₁, R₂, and R₃ is H, and the other two are C₁₋₃alkyl. For example, one of R₁, R₂, and R₃ is H, and the other two aremethyl. In some embodiments, R₁ is H; and R₂ and R₃ together with thenitrogen atoms to which they are attached and the carbon atom connectingthe two nitrogen atoms form a 5- or 6-membered ring. For example, R₁ isH; and R₂ and R₃ together with the nitrogen atoms to which they areattached and the carbon atom connecting the two nitrogen atoms form animidazoline.

In some embodiments of Formula (I), R₄ is H. In some embodiments, R₄ isC₁₋₃ alkyl.

In some embodiments of Formula (I), one of R₅ and R₇ is H and the otheris C₁₋₆ alkyl. For example, R₅ is H and R₇ is C₁₋₆ alkyl. In someembodiments, R₅ and R₇ together with the carbon atoms to which they areattached and the nitrogen atom connecting the two carbon atoms form

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

wherein the ring is optionally substituted on a carbon atom of the ringwith C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted withone or more OH. In some embodiments, R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

In some embodiments of Formula (I), R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form a ring having one of the formulas:

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

wherein the ring is optionally substituted on a carbon atom of the ringwith C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted withone or more OH. In some embodiments, R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

In some embodiments of Formula (I), R₆ and R₇ together with the carbonand nitrogen atoms to which they are attached form a ring of formula

In some embodiments, R₆ and R₇ together with the carbon and nitrogenatoms to which they are attached form a ring of formula

In some embodiments of Formula (I), R₆ and R₇ together with the carbonand nitrogen atoms to which they are attached form a ring having one ofthe formulas:

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH. In some embodiments of Formula (I), R₆ and R₇ together with thecarbon and nitrogen atoms to which they are attached form a ring offormula

In some embodiments, R₆ and R₇ together with the carbon and nitrogenatoms to which they are attached form a ring of formula

In some embodiments of Formula (I), R₆ is selected from H and C₁₋₆ alkyloptionally substituted with one or more substituents selected from thegroup consisting of halogen and OR^(a). In some embodiments, R₆ is H. Insome embodiments, R₆ is C₁₋₆ alkyl optionally substituted with one ormore substituents selected from the group consisting of halogen andOR^(a). For example, R₆ is C₁₋₆ alkyl optionally substituted with one ormore substituents selected from the group consisting of fluorine,bromine and OH.

In some embodiments of Formula (I), R₆ is C₁₋₆ alkyl optionallysubstituted with OR^(a). In some embodiments, R^(a) is H. In someembodiments, R^(a) is C₁₋₆ alkyl.

In some embodiments of Formula (I), R₆ is C₁₋₆ alkyl substituted with—SC(NH)NH₂. In some embodiments, R₆ is C₁₋₆ alkyl optionally substitutedwith halogen. For example, R₆ is C₁₋₆ alkyl optionally substituted withfluoro.

In some embodiments of Formula (I), X is selected from a 5-memberedheterocyclyl ring and phenyl, wherein each of the 5-memberedheterocyclyl ring and phenyl is optionally substituted with one or moreR^(X). For example, X is a 5-membered heterocyclyl ring optionallysubstituted with one or more R^(X). In some embodiments, X is apyrrolidinyl optionally substituted with one or more R^(X). In someembodiments, X is a 2- or 3-pyrrolidinyl optionally substituted with oneor more R^(X). In some embodiments, X is phenyl optionally substitutedwith one or more R^(X). For example, X is phenyl optionally substitutedwith three R^(X).

In some embodiments of Formula (I), R^(X) is independently selected fromhalogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆cycloalkyl, and aryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more R^(b). In some embodiments, R^(X) is independentlyselected from halogen and C₁₋₆ alkyl optionally substituted with one ormore R^(b). In some such embodiments, R^(b) is selected from C₂₋₆alkenyl, OR^(c), N(R^(c))₂, and C₃₋₆ cycloalkyl. For example, R^(b) isselected from C₂₋₆ alkenyl, OR^(c), NH₂, and cyclopropyl. In some suchembodiments, R^(c) is selected from H and C₁₋₆ alkyl. In someembodiments, R^(b) is selected from vinyl, OH, and NH₂. In someembodiments, two adjacent R^(X) come together with the atoms to whichthey are attached to form a 5- or 6-membered ring.

In some embodiments of Formula (I), the compound is a compound ofFormula (IA):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   X is selected from a 5- or 6-membered heterocyclyl ring and phenyl,    wherein each of the 5- or 6-membered heterocyclyl ring and phenyl is    optionally substituted with one or more R^(X);-   R₁ is selected from H and C₁₋₃ alkyl;-   R₂ is selected from H and C₁₋₃ alkyl;-   R₃ is selected from H and C₁₋₃ alkyl;-   R₄ is selected from H and C₁₋₃ alkyl;-   R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the    C₁₋₆ alkyl is optionally substituted with one or more substituents    selected from the group consisting of halogen, OR^(a), SR^(a),    —C(O)OR^(a), —SC(NH)NH₂, C₃₋₆ cycloalkyl, or C₃₋₆ heterocyclyl;-   each R^(X) is independently selected from halogen, C₁₋₆ alkyl, C₁₋₄    haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆    cycloalkyl, and aryl, wherein the C₁₋₆ alkyl is optionally    substituted with one or more R^(b);-   or two adjacent R^(X) come together with the atoms to which they are    attached to form a 5- or 6-membered ring;-   each R^(a) is independently selected from H and C₁₋₆ alkyl;-   each R^(b) is independently selected from C₂₋₆ alkenyl, OR^(c),    N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl;-   each R^(c) is independently selected from H, C₁₋₆ alkyl, aryl,    —C(O)aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are    each optionally substituted with one or more R^(d); and-   each R^(d) is independently selected from C₁₋₃ alkyl, OH, O(C₁₋₃    alkyl), NO₂, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

In some embodiments of Formula (IA), R₁, R₂, and R₃ is H. In someembodiments, two of R₁, R₂, and R₃ are H, and the other is C₁₋₃ alkyl.For example, two of R₁, R₂, and R₃ are H, and the other is methyl. Insome embodiments, one of R₁, R₂, and R₃ is H, and the other two are C₁₋₃alkyl. For example, one of R₁, R₂, and R₃ is H, and the other two aremethyl. In some embodiments, R₂ and R₃ together with the nitrogen atomsto which they are attached and the carbon atom connecting the twonitrogen atoms form a 5- or 6-membered ring. For example, R₂ and R₃together with the nitrogen atoms to which they are attached and thecarbon atom connecting the two nitrogen atoms form an imidazoline.

In some embodiments of Formula (IA), R₄ is H. In some embodiments, R₄ isC₁₋₃ alkyl.

In some embodiments of Formula (IA), R₆ is selected from H and C₁₋₆alkyl optionally substituted with one or more substituents selected fromthe group consisting of halogen and OR^(a). In some embodiments, R₆ isH. In some embodiments, R₆ is C₁₋₆ alkyl optionally substituted with oneor more substituents selected from the group consisting of halogen andOR^(a). For example, R₆ is C₁₋₆ alkyl optionally substituted withOR^(a). In some such embodiments, R^(a) is H. In other such embodiments,R^(a) is C₁₋₆ alkyl. In some embodiments, R₆ is C₁₋₆ alkyl substitutedwith —SC(NH)NH₂. In some embodiments, R₆ is C₁₋₆ alkyl optionallysubstituted with halogen. For example, R₆ is C₁₋₆ alkyl optionallysubstituted with fluoro.

In some embodiments of Formula (IA), X is selected from a 5-memberedheterocyclyl ring and phenyl, wherein each of the 5-memberedheterocyclyl ring and phenyl is optionally substituted with one or moreR^(X). In some embodiments, X is a 5-membered heterocyclyl ringoptionally substituted with one or more R^(X). For example, X is apyrrolidinyl optionally substituted with one or more R^(X). In someembodiments, X is a 2- or 3-pyrrolidinyl optionally substituted with oneor more R^(X). In some embodiments, X is phenyl optionally substitutedwith one or more R^(X). For example, X is phenyl optionally substitutedwith three R^(X).

In some embodiments of Formula (IA), R^(X) is independently selectedfrom halogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c),C₃₋₆ cycloalkyl, and aryl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more R^(b). For example, R^(X) is independentlyselected from halogen and C₁₋₆ alkyl optionally substituted with one ormore R^(b). In some such embodiments, R^(b) is selected from C₂₋₆alkenyl, OR^(c), N(R^(c))₂, and C₃₋₆ cycloalkyl. For example, R^(b) isselected from C₂₋₆ alkenyl, OR^(c), NH₂, and cyclopropyl. In some suchembodiments, R^(c) is selected from H and C₁₋₆ alkyl. In someembodiments, R^(b) is selected from vinyl, OH, and NH₂.

In some embodiments of Formula (IA), two adjacent R^(X) come togetherwith the atoms to which they are attached to form a 5- or 6-memberedring.

In some embodiments of Formula (I), the compound is a compound ofFormula (IB).

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   X is selected from a 5- or 6-membered heterocyclyl ring and phenyl,    wherein each of the 5- or 6-membered heterocyclyl ring and phenyl is    optionally substituted with one or more R^(X);-   each R^(X) is independently selected from halogen, C₁₋₆ alkyl, C₁₋₄    haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆    cycloalkyl, and aryl, wherein the C₁₋₆ alkyl is optionally    substituted with one or more R^(b);-   or two adjacent R^(X) come together with the atoms to which they are    attached to form a 5- or 6-membered ring;-   each R^(b) is independently selected from C₂₋₆ alkenyl, OR^(c),    N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl;-   each R^(c) is independently selected from H, C₁₋₆ alkyl, aryl,    —C(O)aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are    each optionally substituted with one or more R^(d); and-   each R^(d) is independently selected from C₁₋₃ alkyl, OH, O(C₁₋₃    alkyl), NO₂, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

In some embodiments of Formula (IB), X is selected from a 5-memberedheterocyclyl ring and phenyl, wherein each of the 5-memberedheterocyclyl ring and phenyl is optionally substituted with one or moreR^(X). In some embodiments, X is a 5-membered heterocyclyl ringoptionally substituted with one or more R^(X). For example, X is apyrrolidinyl optionally substituted with one or more R^(X). In someembodiments, X is a 2- or 3-pyrrolidinyl optionally substituted with oneor more R^(X). In some embodiments, X is phenyl optionally substitutedwith one or more R^(X). For example, X is phenyl optionally substitutedwith three R^(X). In some embodiments, R^(X) is independently selectedfrom halogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c),C₃₋₆ cycloalkyl, and aryl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more R^(b). In some embodiments, R^(X) isindependently selected from halogen and C₁₋₆ alkyl optionallysubstituted with one or more R^(b). In some embodiments, R^(b) isselected from C₂₋₆ alkenyl, OR^(c), N(R^(c))₂, and C₃₋₆ cycloalkyl. Forexample, R^(b) is selected from C₂₋₆ alkenyl, OR^(c), NH₂, andcyclopropyl. In some such embodiments, R^(c) is selected from H and C₁₋₆alkyl. In some embodiments, R^(b) is selected from vinyl, OH, and NH₂.

In some embodiments of Formula (IB), two adjacent R^(X) come togetherwith the atoms to which they are attached to form a 5- or 6-memberedring.

Also provided herein is a compound of Formula (II):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   R₁ is selected from H and C₁₋₃ alkyl;-   R₂ is selected from H and C₁₋₃ alkyl;-   R₃ is selected from H and C₁₋₃ alkyl;-   or R₂ and R₃ together with the nitrogen atoms to which they are    attached and the carbon atom connecting the two nitrogen atoms form    a 5- or 6-membered ring;-   R₄ is selected from H and C₁₋₃ alkyl;-   R₅ is selected from H and C₁₋₆ alkyl;-   R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the    C₁₋₆ alkyl is optionally substituted with one or more substituents    selected from the group consisting of halogen, OR^(a), SR^(a),    —C(O)OR^(a), —SC(NH)NH₂, C₃₋₆ cycloalkyl, or C₃₋₆ heterocyclyl;-   R₇ is selected from H and C₁₋₆ alkyl;-   or R₆ and R₇ together with the carbon and nitrogen atoms to which    they are attached form a ring having one of the formulas:

-   wherein the ring is optionally substituted on a ring carbon atom    with C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted    with one or more OH;-   or R₅ and R₇ together with the carbon atoms to which they are    attached and the nitrogen atom connecting the two carbon atoms form    a ring having one of the formulas:

-   R₈ is selected from H and halogen;-   R₉ is selected from H and halogen;-   R₁₀ is selected from H, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and    C₃₋₆ cycloalkyl;-   R₁₁ is selected from C₁₋₃ alkyl, C₂₋₄ alkenyl, and C₃₋₆ cycloalkyl,    wherein the C₁₋₃ alkyl is optionally substituted with one or more    R^(b);-   R₁₇ is selected from H, halogen, and C₁₋₆ alkyl;-   each R^(a) is independently selected from H and C₁₋₆ alkyl;-   each R^(b) is independently selected from OR^(c), —C(O)OR^(c), and    —(O)aryl, wherein the aryl is optionally substituted with one or    more R^(d);-   each R^(c) is independently selected from hydrogen, C₁₋₃ alkyl, OH,    O(C₁₋₃ alkyl), NO₂, —C(O)aryl, and aryl; and-   each R^(d) is C₁₋₃ alkyl.

In some embodiments of Formula (II), each of R₁, R₂, and R₃ is H. Insome embodiments, two of R₁, R₂, and R₃ are H, and the other is C₁₋₃alkyl. For example, two of R₁, R₂, and R₃ are H, and the other ismethyl. In some embodiments, one of R₁, R₂, and R₃ is H, and the othertwo are C₁₋₃ alkyl. For example, one of R₁, R₂, and R₃ is H, and theother two are methyl. In some embodiments, R₂ and R₃ together with thenitrogen atoms to which they are attached and the carbon atom connectingthe two nitrogen atoms form a 5- or 6-membered ring. For example, R₂ andR₃ together with the nitrogen atoms to which they are attached and thecarbon atom connecting the two nitrogen atoms form an imidazoline.

In some embodiments of Formula (II), R₄ is H. In some embodiments, R₄ isC₁₋₃ alkyl.

In some embodiments of Formula (II), one of R₅ and R₇ is H and the otheris C₁₋₆ alkyl. For example, R₅ is H and R₇ is C₁₋₆ alkyl. In someembodiments, R₅ and R₇ together with the carbon atoms to which they areattached and the nitrogen atom connecting the two carbon atoms form

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

wherein the ring is optionally substituted on a carbon atom of the ringwith C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted withone or more OH. In some embodiments, R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

In some embodiments of Formula (II), R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form a ring having one of the formulas:

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

wherein the ring is optionally substituted on a carbon atom of the ringwith C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted withone or more OH. In some embodiments, R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

In some embodiments of Formula (II), R₆ and R₇ together with the carbonand nitrogen atoms to which they are attached form a ring of formula

In some embodiments, R₆ and R₇ together with the carbon and nitrogenatoms to which they are attached form a ring of formula

In some embodiments of Formula (II), R₆ and R₇ together with the carbonand nitrogen atoms to which they are attached form a ring-having one ofthe formulas:

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH. In some embodiments, R₆ and R₇ together with the carbon andnitrogen atoms to which they are attached form a ring of formula

In some embodiments, R₆ and R₇ together with the carbon and nitrogenatoms to which they are attached form a ring of formula

In some embodiments of Formula (II), R₆ is selected from H and C₁₋₆alkyl optionally substituted with one or more substituents selected fromthe group consisting of halogen and OR^(a). In some embodiments, R₆ isH. In some embodiments, R₆ is C₁₋₆ alkyl optionally substituted with oneor more substituents selected from the group consisting of halogen andOR^(a). In some embodiments, R₆ is C₁₋₆ alkyl optionally substitutedwith OR. In some such embodiments, R^(a) is H. In other suchembodiments, R^(a) is C₁₋₆ alkyl. In some embodiments, R₆ is C₁₋₆ alkylsubstituted with —SC(NH)NH₂. In some embodiments, R₆ is C₁₋₆ alkyloptionally substituted with halogen. For example, R₆ is C₁₋₆ alkyloptionally substituted with fluoro.

In some embodiments of Formula (II), R₈ is H. In some embodiments, R₈ ishalogen. For example, R₈ is F.

In some embodiments of Formula (II), one of R₉ and R₁₀ is halogen andthe other is H. In some embodiments, each of R₉ and R₁₀ is halogen. Forexample, R₉ is fluoro and R₁₀ is chloro. In some embodiments, R₉ is Hand R₁₀ is C₁₋₄ alkyl. In some embodiments, R₉ is halogen and R₁₀ isC₁₋₄ alkyl. For example, R₉ is chloro and R₁₀ is C₁₋₄ alkyl. In someembodiments, R₉ is fluoro and R₁₀ is C₁₋₄ alkyl. In some suchembodiments, R₁₀ is ethyl or R₁₀ is isopropyl. In some embodiments, R₉is H and R₁₀ is C₃₋₆ cycloalkyl. For example, R₁₀ is cyclopropyl or R₁₀is cyclopentyl.

In some embodiments of Formula (II), R₁₁ is selected from C₁₋₃ alkyloptionally substituted with one or more R^(b), and C₂₋₄ alkenyl. In someembodiments, R₁₁ is selected from C₁₋₃ alkyl optionally substituted withone or more R, and C₃₋₆ cycloalkyl. In some embodiments, R₁₁ is C₁₋₃alkyl optionally substituted with one or more R^(b). In some suchembodiments, R^(b) is OR^(c), wherein R^(c) is selected from H and C₁₋₃alkyl. For example, R^(c) is H. In some embodiments, R^(c) is C₁₋₃alkyl. In some embodiments, R₁₁ is C₁₋₃ alkyl. For example, R₁₁ ismethyl. In some embodiments, R₁₁ is C₃₋₆ cycloalkyl. For example, R₁₁ iscyclopropyl.

In some embodiments of Formula (II), the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₁ is bonded to is (R). In someembodiments, the Cahn-Ingold-Prelog configuration at the carbon atom R₁₁is bonded to is (S).

In some embodiments, R₁₇ is H. In some embodiments, R₁₇ is halogen.

In some embodiments of Formula (II), each of R₉ and R₁₀ is halogen, andR₁₁ is C₁₋₃ alkyl optionally substituted with one or more R^(b). Forexample, R₉ is fluoro, R₁₀ is chloro, and R₁₁ is C₁₋₃ alkyl optionallysubstituted with one or more R^(b). In some embodiments, R₉ is fluoro,R₁₀ is chloro, and R₁₁ is methyl. In some embodiments, R₉ is fluoro, R₁₀is chloro, R₁₁ is methyl, and wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₁ is bonded to is (S).

In some embodiments of Formula (II), each of R₁, R₂, and R₃ is H; R₄ isH; R₆ is C₁₋₆ alkyl optionally substituted with one or more substituentsselected from the group consisting of halogen and OR^(a); R₉ is fluoro,R₁₀ is chloro, and R₁₁ is methyl. In some embodiments, each of R₁, R₂,and R₃ is H; R₄ is H; R₆ is H or C₁₋₆ alkyl; R₉ is fluoro, R₁₀ ischloro, R₁₁ is methyl, and wherein the Cahn-Ingold-Prelog configurationat the carbon atom R₁₁ is bonded to is (S). In some embodiments, each ofR₁, R₂, and R₃ is H; R₄ is H; R₆ and R₇ together with the carbon andnitrogen atoms to which they are attached form a ring of formula

R₉ is fluoro; R₁₀ is chloro; and R₁₁ is methyl. In some embodiments,each of R₁, R₂, and R₃ is H; R₄ is H; R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form

R₆ is H or C₁₋₆ alkyl; R₉ is fluoro, R₁₀ is chloro, R₁₁ is methyl, andwherein the Cahn-Ingold-Prelog configuration at the carbon atom R₁₁ isbonded to is (S).

In some embodiments of Formula (II), the compound is a compound ofFormula (IIA):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   R₁ is selected from H and C₁₋₃ alkyl;-   R₂ is selected from H and C₁₋₃ alkyl;-   R₃ is selected from H and C₁₋₃ alkyl;-   R₄ is selected from H and C₁₋₃ alkyl;-   R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the    C₁₋₆ alkyl is optionally substituted with one or more substituents    selected from the group consisting of halogen and OR^(a);-   R₉ is selected from H and halogen;-   R₁₀ is selected from H, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and    C₃₋₆ cycloalkyl-   R₁₁ is selected from C₁₋₃ alkyl, C₂₋₄ alkenyl, and C₃₋₆ cycloalkyl,    wherein the C₁₋₃ alkyl is optionally substituted with one or more    R^(b);    -   each R^(a) is independently selected from H and C₁₋₆ alkyl;    -   each R^(b) is independently selected from OR^(c), —C(O)OR^(c),        and —(O)aryl, wherein the aryl is optionally substituted with        one or more R^(d);    -   each R^(c) is independently selected from hydrogen, C₁₋₃ alkyl,        OH, O(C₁₋₃ alkyl), NO₂, —C(O)aryl, and aryl; and each R^(d) is        C₁₋₃ alkyl.

In some embodiments of Formula (IIA), each of R₁, R₂, and R₃ is H. Insome embodiments, two of R₁, R₂, and R₃ are H, and the other is C₁₋₃alkyl. For example, two of R₁, R₂, and R₃ are H, and the other ismethyl. In some embodiments, one of R₁, R₂, and R₃ is H, and the othertwo are C₁₋₃ alkyl. For example, one of R₁, R₂, and R₃ is H, and theother two are methyl. In some embodiments, R₂ and R₃ together with thenitrogen atoms to which they are attached and the carbon atom connectingthe two nitrogen atoms form a 5- or 6-membered ring. For example, R₂ andR₃ together with the nitrogen atoms to which they are attached and thecarbon atom connecting the two nitrogen atoms form an imidazoline.

In some embodiments of Formula (IIA), R₄ is H.

In some embodiments of Formula (IIA), R₆ is selected from H and C₁₋₆alkyl optionally substituted with one or more substituents selected fromthe group consisting of halogen and OR^(a). In some embodiments, R₆ isH. In some embodiments, R₆ is C₁₋₆ alkyl optionally substituted with oneor more substituents selected from the group consisting of halogen andOR^(a). For example, R₆ is C₁₋₆ alkyl optionally substituted withOR^(a). In some such embodiments, R^(a) is H. In other such embodiments,R^(a) is C₁₋₆ alkyl. In some embodiments, R₆ is C₁₋₆ alkyl optionallysubstituted with halogen. For example, R₆ is C₁₋₆ alkyl optionallysubstituted with fluoro.

In some embodiments of Formula (IIA), one of R₉ and R₁₀ is halogen andthe other is H. In some embodiments, each of R₉ and R₁₀ is halogen. Forexample, R₉ is fluoro and R₁₀ is chloro. In some embodiments, R₉ is Hand R₁₀ is C₁₋₄ alkyl. In some embodiments, R₉ is halogen and R₁₀ isC₁₋₄ alkyl. For example, R₉ is chloro and R₁₀ is C₁₋₄ alkyl. In someembodiments, R₉ is fluoro and R₁₀ is C₁₋₄ alkyl. For example, R₁₀ isethyl or R₁₀ is isopropyl. In some embodiments, R₉ is H and R₁₀ is C₃₋₆cycloalkyl. For example, R₁₀ is cyclopropyl or R₁₀ is cyclopentyl.

In some embodiments of Formula (IIA), R₁₁ is selected from C₁₋₃ alkyloptionally substituted with one or more R, and C₂₋₄ alkenyl. In someembodiments, R₁₁ is selected from C₁₋₃ alkyl optionally substituted withone or more R, and C₃₋₆ cycloalkyl. In some embodiments, R₁₁ is C₁₋₃alkyl optionally substituted with one or more R^(b). In some suchembodiments, R^(b) is OR^(c), and wherein R^(c) is selected from H andC₁₋₃ alkyl. For example, R^(c) is H. In some embodiments, R^(c) is C₁₋₃alkyl. In some embodiments, R₁₁ is C₁₋₃ alkyl. For example, R₁₁ ismethyl. In some embodiments, R₁₁ is C₃₋₆ cycloalkyl. For example, R₁₁ iscyclopropyl.

In some embodiments of Formula (IIA), the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₁ is bonded to is (R). In someembodiments, the Cahn-Ingold-Prelog configuration at the carbon atom R₁₁is bonded to is (S).

In some embodiments of Formula (IIA), each of R₉ and R₁₀ is halogen, andR₁₁ is C₁₋₃ alkyl optionally substituted with one or more R^(b). Forexample, R₉ is fluoro, R₁₀ is chloro, and R₁₁ is C₁₋₃ alkyl optionallysubstituted with one or more R^(b). In some embodiments, R₉ is fluoro,R₁₀ is chloro, and R₁₁ is methyl. In some embodiments, R₉ is fluoro, R₁₀is chloro, R₁₁ is methyl, and wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₁ is bonded to is (S).

In some embodiments of Formula (IIA), each of R₁, R₂, and R₃ is H; R₄ isH; R₆ is C₁₋₆ alkyl optionally substituted with one or more substituentsselected from the group consisting of halogen and OR^(a); R₉ is fluoro,R₁₀ is chloro, and R₁₁ is methyl. In some embodiments, each of R₁, R₂,and R₃ is H; R₄ is H; R₆ is H or C₁₋₆ alkyl; R₉ is fluoro, R₁₀ ischloro, R₁₁ is methyl, and wherein the Cahn-Ingold-Prelog configurationat the carbon atom R₁₁ is bonded to is (S).

In some embodiments of Formula (II), the compound is a compound ofFormula (IIB):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   R₉ is selected from H and halogen;-   R₁₀ is selected from H, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and    C₃₋₆ cycloalkyl;-   R₁₁ is selected from C₁₋₃ alkyl, C₂₋₄ alkenyl, and C₃₋₆ cycloalkyl,    wherein the C₁₋₃ alkyl is optionally substituted with one or more    R^(b);-   each R^(b) is independently selected from OR^(c), —C(O)OR^(c), and    —(O)aryl, wherein the aryl is optionally substituted with one or    more R^(d);-   each R^(c) is independently selected from hydrogen, C₁₋₃ alkyl, OH,    O(C₁₋₃ alkyl), NO₂, —C(O)aryl, and aryl; and-   each R^(d) is C₁₋₃ alkyl.

In some embodiments of Formula (IIB), one of R₉ and R₁₀ is halogen andthe other is H. In some embodiments, each of R₉ and R₁₀ is halogen. Forexample, R₉ is fluoro and R₁₀ is chloro. In some embodiments, R₉ is Hand R₁₀ is C₁₋₄ alkyl. In some embodiments, R₉ is halogen and R₁₀ isC₁₋₄ alkyl. For example, R₉ is chloro and R₁₀ is C₁₋₄ alkyl. In someembodiments, R₉ is fluoro and R₁₀ is C₁₋₄ alkyl. For example, R₁₀ isethyl or R₁₀ is isopropyl. In some embodiments, R₉ is H and R₁₀ is C₃₋₆cycloalkyl. For example, R₁₀ is cyclopropyl or R₁₀ is cyclopentyl.

In some embodiments of Formula (IIB), R₁₁ is selected from C₁₋₃ alkyloptionally substituted with one or more R^(b), and C₂₋₄ alkenyl. In someembodiments, R₁₁ is selected from C₁₋₃ alkyl optionally substituted withone or more R, and C₃₋₆ cycloalkyl. In some embodiments, R₁₁ is C₁₋₃alkyl optionally substituted with one or more R^(b). In some suchembodiments, R^(b) is OR^(c), and R^(c) is selected from H and C₁₋₃alkyl. For example, R^(c) is H. In some embodiments, R^(c) is C₁₋₃alkyl. In some embodiments, R₁₁ is C₁₋₃ alkyl. For example, R₁₁ ismethyl. In some embodiments, R₁₁ is C₃₋₆ cycloalkyl. For example, R₁₁ iscyclopropyl.

In some embodiments of Formula (IIB), the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₁ is bonded to is (R). In someembodiments, the Cahn-Ingold-Prelog configuration at the carbon atom R₁₁is bonded to is (S).

In some embodiments of Formula (IIB), each of R₉ and R₁₀ is halogen, andR₁₁ is C₁₋₃ alkyl optionally substituted with one or more R^(b). Forexample, R₉ is fluoro, R₁₀ is chloro, and R₁₁ is C₁₋₃ alkyl optionallysubstituted with one or more R^(b). In some embodiments, R₉ is fluoro,R₁₀ is chloro, and R₁₁ is methyl. In some embodiments, R₉ is fluoro, R₁₀is chloro, R₁₁ is methyl, and wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₁ is bonded to is (S).

Also provided herein is a compound of Formula (III).

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   R₁ is selected from H and C₁₋₃ alkyl;-   R₂ is selected from H and C₁₋₃ alkyl;-   R₃ is selected from H and C₁₋₃ alkyl;-   or R₂ and R₃ together with the nitrogen atoms to which they are    attached and the carbon atom connecting the two nitrogen atoms form    a 5- or 6-membered ring;-   R₄ is selected from H and C₁₋₃ alkyl;-   R₅ is selected from H and C₁₋₆ alkyl;-   R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the    C₁₋₆ alkyl is optionally substituted with one or more substituents    selected from the group consisting of halogen, OR^(a), SR^(a),    —C(O)OR^(a), and —SC(NH)NH₂;-   R₇ is selected from H and C₁₋₆ alkyl;-   or R₆ and R₇ together with the carbon and nitrogen atoms to which    they are attached form a ring having one of the formulas:

-   wherein the ring is optionally substituted on a carbon atom with    C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with    one or more OH;-   or R₅ and R₇ together with the carbon atoms to which they are    attached and the nitrogen atom connecting the two carbon atoms form    a ring having one of the formulas:

-   R₈ is selected from H and halogen;-   R₁₂ is selected from H, halogen, and C₁₋₆ alkyl;-   R₁₃ is selected from H, halogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂,    wherein C₁₋₆ alkyl is optionally substituted with one or more of OR    and aryl;-   R₁₄ is selected from H and aryl;-   or R₁₃ and R₁₄ together with the carbon atoms to which they are    attached form a 5- or 6-membered cycloalkyl ring;-   R₁₅ is selected from H, C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is    optionally substituted with one or more R^(b).-   each R^(a) is independently selected from H and C₁₋₆ alkyl;-   each R^(b) is independently selected from C₂₋₆ alkenyl, OR^(c),    N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl;-   each R^(c) is independently selected from hydrogen, C₁₋₆ alkyl,    aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are each    optionally substituted with one or more R^(d); and-   each R^(d) is independently selected from OH, O(C₁₋₃ alkyl), NH₂,    NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

In some embodiments of Formula (III), each of R₁, R₂, and R₃ is H. Insome embodiments, two of R₁, R₂, and R₃ are H, and the other is C₁₋₃alkyl. For example, two of R₁, R₂, and R₃ are H, and the other ismethyl. In some embodiments, one of R₁, R₂, and R₃ is H, and the othertwo are C₁₋₃ alkyl. For example, one of R₁, R₂, and R₃ is H, and theother two are methyl.

In some embodiments of Formula (III), R₄ is H.

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

wherein the ring is optionally substituted on a carbon atom of the ringwith C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted withone or more OH. In some embodiments, R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

In some embodiments of Formula (III), R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form a ring having one of the formulas:

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

wherein the ring is optionally substituted on a carbon atom of the ringwith C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted withone or more OH. In some embodiments, R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form

In some embodiments, R₅ and R₇ together with the carbon atoms to whichthey are attached and the nitrogen atom connecting the two carbon atomsform

In some embodiments of Formula (III), R₆ and R₇ together with the carbonand nitrogen atoms to which they are attached form a ring of formula

In some embodiments, R₆ and R₇ together with the carbon and nitrogenatoms to which they are attached form a ring of formula

In some embodiments of Formula (III), R₆ and R₇ together with the carbonand nitrogen atoms to which they are attached form a ring having one ofthe formulas:

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH. In some embodiments, R₆ and R₇ together with the carbon andnitrogen atoms to which they are attached form a ring of formula

In some embodiments, R₆ and R₇ together with the carbon and nitrogenatoms to which they are attached form a ring of formula

In some embodiments of Formula (III), R₆ is selected from H or C₁₋₆alkyl optionally substituted with one or more substituents selected fromthe group consisting of halogen, OR^(a), SR^(a), —C(O)OR^(a), and—SC(NH)NH₂. In some embodiments, R₆ is H.

In some embodiments of Formula (III), R₈ is H. In some embodiments, R₈is halogen. For example, R₈ is F.

In some embodiments of Formula (III), each of R₁₂ and R₁₃ is H. In someembodiments, each of R₁₂ and R₁₃ is not H. In some embodiments, one ofR₁₂ and R₁₃ is H, and the other is not H. For example, R₁₂ is H, and R₁₃is C₁₋₆ alkyl optionally substituted with one or more of OR^(c) or aryl.In some embodiments, R₁₂ is H, and R₁₃ is C₁₋₆ alkyl optionallysubstituted with OR^(c). In some embodiments, R₁₂ is H, and R₁₃ is C₁₋₆alkyl. In some embodiments, R₁₂ is H, and R₁₃ is halogen. In someembodiments, R₁₂ is H, and R₁₃ is fluoro. In some embodiments, each ofR₁₂ and R₁₃ is C₁₋₆ alkyl. In some embodiments, each of R₁₂ and R₁₃ ishalogen. For example, each of R₁₂ and R₁₃ is fluoro. In someembodiments, R₁₂ is H, and R₁₃ is OR^(c). In some embodiments, R₁₂ is H,and R₁₃ is N(R^(c))₂. In some such embodiments, each R^(c) is selectedfrom H or C₁₋₆ alkyl. In some other such embodiments, one R^(c) is H andthe other R^(c) is C₁₋₆ alkyl.

In some embodiments of Formula (III), each R^(c) is selected from H orC₁₋₆ alkyl. In some embodiments, each R^(c) is selected from C₁₋₆ alkylor —(CH₂)aryl. In some embodiments, each R^(c) is H. In someembodiments, each R^(c) is C₁₋₆ alkyl. For example, each R^(c) ismethyl. In some embodiments, each R^(c) is —(CH₂)aryl.

In some embodiments of Formula (III), the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₃ is bonded to is (R). In someembodiments, the Cahn-Ingold-Prelog configuration at the carbon atom R₁₃is bonded to is (S).

In some embodiments of Formula (III), R₁₄ is H. In some embodiments, R₁₄is aryl. In some embodiments, the Cahn-Ingold-Prelog configuration atthe carbon atom R₁₄ is bonded to is (R). In some embodiments, theCahn-Ingold-Prelog configuration at the carbon atom R₁₄ is bonded to is(S).

In some embodiments of Formula (III), R₁₅ is H. In some embodiments, R₁₅is C₁₋₆ alkyl optionally substituted with one or more R^(b). Forexample, R₁₅ is C₁₋₆ alkyl optionally substituted with one R^(b). Insome embodiments, R₁₅ is C₄₋₅ alkyl optionally substituted with oneR^(b).

In some embodiments of Formula (III), R^(b) is selected from OR^(c),N(R^(c))₂, and cyclopropyl. For example, R^(b) is N(R^(c))₂. In someembodiments, R^(b) is NH₂.

In some embodiments of Formula (III), the compound is a compound ofFormula (IIIA):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   R₁ is selected from H and C₁₋₃ alkyl;-   R₂ is selected from H and C₁₋₃ alkyl;-   R₃ is selected from H and C₁₋₃ alkyl;-   R₄ is selected from H and C₁₋₃ alkyl;-   R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the    C₁₋₆ alkyl is optionally substituted with one or more substituents    selected from the group consisting of halogen, OR^(a), SR^(a),    —C(O)OR^(a), and —SC(NH)NH₂;-   R₈ is selected from H and halogen;-   R₁₂ is selected from H, halogen, and C₁₋₆ alkyl;-   R₁₃ is selected from H, halogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂,    wherein C₁₋₆ alkyl is optionally substituted with one or more of    OR^(c) and aryl; R₁₄ is selected from H and aryl;-   or R₁₃ and R₁₄ together with the carbon atoms to which they are    attached form a 5- or 6-membered cycloalkyl ring;-   R₁₆ is C₁₋₆ alkyl;-   each R^(a) is independently selected from H and C₁₋₆ alkyl;-   each R^(c) is independently selected from hydrogen, C₁₋₆ alkyl,    aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are each    optionally substituted with one or more R^(d); and-   each R^(d) is independently selected from OH, O(C₁₋₃ alkyl), NH₂,    NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

In some embodiments of Formula (IIIA), each of R₁, R₂, and R₃ is H. Insome embodiments, two of R₁, R₂, and R₃ are H, and the other is C₁₋₃alkyl. For example, two of R₁, R₂, and R₃ are H, and the other ismethyl. In some embodiments, one of R₁, R₂, and R₃ is H, and the othertwo are C₁₋₃ alkyl. For example, one of R₁, R₂, and R₃ is H, and theother two are methyl.

In some embodiments of Formula (IIIA), R₄ is H.

In some embodiments of Formula (IIIA), R₆ is selected from H or C₁₋₆alkyl optionally substituted with one or more substituents selected fromthe group consisting of halogen, OR^(a), SR^(a), —C(O)OR^(a), or—SC(NH)NH₂. In some embodiments, R₆ is H.

In some embodiments of Formula (IIIA), R₈ is H. In some embodiments, R₈is halogen. For example, R₈ is F.

In some embodiments, of Formula (IIIA), each of R₁₂ and R₁₃ is H. Insome embodiments, each of R₁₂ and R₁₃ is not H. In some embodiments, oneof R₁₂ and R₁₃ is H, and the other is not H. For example, R₁₂ is H, andR₁₃ is C₁₋₆ alkyl optionally substituted with one or more of OR^(c) oraryl. In some embodiments, R₁₂ is H, and R₁₃ is C₁₋₆ alkyl optionallysubstituted with OR. In some embodiments, R₁₂ is H, and R₁₃ is C₁₋₆alkyl. In some embodiments, R₁₂ is H, and R₁₃ is halogen. For example,R₁₂ is H, and R₁₃ is fluoro. In some embodiments, each of R₁₂ and R₁₃ isC₁₋₆ alkyl. In some embodiments, each of R₁₂ and R₁₃ is halogen. Forexample, each of R₁₂ and R₁₃ is fluoro. In some embodiments, R₁₂ is H,and R₁₃ is OR. In some embodiments, R₁₂ is H, and R₁₃ is N(R^(c))₂. Insome such embodiments, each R^(c) is selected from H or C₁₋₆ alkyl. Inother such embodiments, one R^(c) is H and the other R^(c) is C₁₋₆alkyl.

In some embodiments of Formula (IIIA), each R^(c) is selected from H orC₁₋₆ alkyl. In some embodiments, R^(c) is selected from C₁₋₆ alkyl or—(CH₂)aryl. In some embodiments, R^(c) is H. In some embodiments, R^(c)is C₁₋₆ alkyl. For example, R^(c) is methyl. In some embodiments, R^(c)is —(CH₂)aryl. For example, R^(c) is —(CH₂)phenyl.

In some embodiments of Formula (IIIA), the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₃ is bonded to is (R). In someembodiments, the Cahn-Ingold-Prelog configuration at the carbon atom R₁₃is bonded to is (S).

In some embodiments of Formula (IIIA), R₁₄ is H. In some embodiments,R₁₄ is aryl. In some embodiments, the Cahn-Ingold-Prelog configurationat the carbon atom R₁₄ is bonded to is (R). In some embodiments, theCahn-Ingold-Prelog configuration at the carbon atom R₁₄ is bonded to is(S).

In some embodiments of Formula (IIIA), R₁₆ is C₁₋₆ alkyl. For example,R₁₆ is methyl. In some embodiments, the Cahn-Ingold-Prelog configurationat the carbon atom R₁₆ is bonded to is (S). In some embodiments, theCahn-Ingold-Prelog configuration at the carbon atom R₁₆ is bonded to is(R).

In some embodiments of Formula (III), the compound is a compound ofFormula (IIIB):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein:

-   R₁₂ is selected from H, halogen, and C₁₋₆ alkyl;-   R₁₃ is selected from H, halogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂,    wherein C₁₋₆ alkyl is optionally substituted with one or more of    OR^(c) and aryl;-   R₁₆ is C₁₋₆ alkyl;-   each R^(c) is independently selected from hydrogen, C₁₋₆ alkyl,    aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are each    optionally substituted with one or more R^(d); and-   each R^(d) is independently selected from OH, O(C₁₋₃ alkyl), NH₂,    NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.

In some embodiments of Formula (IIIB), each of R₁₂ and R₁₃ is H. In someembodiments, each of R₁₂ and R₁₃ is not H. In some embodiments, one ofR₁₂ and R₁₃ is H, and the other is not H. In some embodiments, R₁₂ is H,and R₁₃ is C₁₋₆ alkyl optionally substituted with one or more of OR^(c)or aryl. In some embodiments, R₁₂ is H, and R₁₃ is C₁₋₆ alkyl optionallysubstituted with OR^(c). In some embodiments, R₁₂ is H, and R₁₃ is C₁₋₆alkyl. In some embodiments, R₁₂ is H, and R₁₃ is halogen. For example,R₁₂ is H, and R₁₃ is fluoro. In some embodiments, each of R₁₂ and R₁₃ isC₁₋₆ alkyl. In some embodiments, each of R₁₂ and R₁₃ is halogen. Forexample, each of R₁₂ and R₁₃ is fluoro. In some embodiments, R₁₂ is H,and R₁₃ is OR^(c). In some embodiments, R₁₂ is H, and R₁₃ is N(R^(c))₂.

In some embodiments of Formula (IIIB), each R^(c) is selected from H orC₁₋₆ alkyl. In some embodiments, each R^(c) is selected from C₁₋₆ alkylor —(CH₂)aryl. In some embodiments, each R^(c) is H. In someembodiments, each R^(c) is C₁₋₆ alkyl. For example, each R^(c) ismethyl. In some embodiments, each R^(c) is —(CH₂)aryl.

In some embodiments of Formula (IIIB), the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₃ is bonded to is (R). In someembodiments, the Cahn-Ingold-Prelog configuration at the carbon atom R₁₃is bonded to is (S).

In some embodiments of Formula (IIIB), R₁₆ is C₁₋₆ alkyl. For example,R₁₆ is methyl. In some embodiments, the Cahn-Ingold-Prelog configurationat the carbon atom R₁₆ is bonded to is (S). In some embodiments, theCahn-Ingold-Prelog configuration at the carbon atom R₁₆ is bonded to is(R).

In some embodiments, one of R₁₂ and R₁₃ is H, and the other of R₁₂ andR₁₃ is not H; and R₁₆ is methyl, wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₆ is bonded to is (S). In someembodiments, R₁₂ is H, and R₁₃ is OR^(c); R^(c) is selected from H orC₁₋₆ alkyl; and R₁₆ is methyl, wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₆ is bonded to is (S).

In some embodiments of Formula (I), Formula (II), or Formula (III), thepresent disclosure provides any one of compounds listed in Table 1, or atautomer thereof or a pharmaceutically acceptable salt of the compoundor tautomer.

TABLE 1 ESI, MW m/z # Structure (g/mol) [M + H]⁺ 1

636.24 636.7 2

636.24 636.3 3

662.27 662.3 4

670.27 670.5 5

696.31 696.5 6

668.28 668.5 7

694.32 694.5 8

626.20 626.4 9

584.16 584.4 10

730.30 730.5 11

624.23 624.5 12

624.23 624.5 13

650.26 650.5 14

622.21 622.4 15

648.25 648.5 16

608.18 608.5 17

668.28 668.5 18

694.32 694.5 19

726.39 726.5 20

752.42 752.5 21

628.19 628.4 22

644.19 644.4 23

582.14 582 24

582.14 582 25

654.23 654.4 26

598.19 598.5 27

610.20 610.5 28

611.18 611.5 29

596.17 596 30

612.17 612 31

550.77 551 32

550.77 551 33

564.80 565 34

610.20 610.3 35

702.30 702.5 36

640.20 640.4 37

596.17 596 38

612.17 612 39

732.32 732.5 40

716.32 716.4 41

624.23 624.5 42

624.23 624.5 43

638.25 638.4 44

638.25 638.3 45

622.21 622.3 46

650.26 650.4 47

552.74 553 48

747.29 747.4 49

571.75 572 50

636.24 636.5 51

519.71 520 52

624.23 624.5 53

604.86 605.5 54

568.12 568 55

568.12 568 56

652.28 652.5 57

580.80 581 58

562.78 563 59

622.21 622.5 60

552.74 553 61

479.65 480 62

604.86 605 63

656.90 657 64

566.78 567 65

565.79 566 66

579.81 580 67

564.80 565 68

564.80 565 69

568.76 569 70

568.76 569 71

586.75 587 72

586.75 587 73

562.78 563 74

578.83 579 75

548.76 549 76

640.90 641 77

626.87 627 78

624.23 624.5 79

624.23 624.5 80

640.22 640.2 81

580.80 581 82

620.26 620.4 83

494.66 495 84

617.83 618.5 85

603.81 604.5 86

613.87 614.5 87

585.82 586.3 88

480.64 481 89

621.80 622 90

666.31 666 91

684.34 684 92

599.80 600 93

611.85 612.4 94

664.29 664 95

745.20 746 96

682.26 682 97

668.28 668 98

656.24 656 99

597.83 598.5 100

625.87 626 101

682.29 682 102

722.36 722 103

678.31 678 104

621.79 622 105

682.29 682 106

640.22 640.5 107

625.88 626.0 108

682.30 682.0 109

722.37 722.0 110

678.31 678.0 111

624.22 624.5 112

621.8 622.0 113

682.30 682.0 114

596.17 596.4 115

624.18 624.5 116

596.17 596.4 117

656.24 656.8 118

638.25 638.0 119

652.27 652.0 120

624.22 624.0 121

642.21 642.5 122

650.26 650.4 123

636.23 636.4

In Table 1 above, a bond indicated by a squiggle bond indicates astereoisomer where the identity of the specific orientation of the bondhas not been specified.

In some embodiments, the present disclosure relates to a compound or atautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer that binds the ribosome. In some embodiments, the ribosomeis a bacterial ribosome.

In some embodiments, the present disclosure relates to a pharmaceuticalcomposition comprising a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of the compound ortautomer, and a pharmaceutically acceptable carrier. In someembodiments, the present disclosure relates to a compound or a tautomerthereof, or a pharmaceutically acceptable salt of the compound ortautomer disclosed herein and a means for delivery.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of or delaying the onset of adisease state in a human or animal comprising administering to the humanor animal in need thereof an effective amount of a compound disclosedherein, or a tautomer thereof, or a pharmaceutically acceptable salt ofthe compound or tautomer.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer.

In some embodiments, the present disclosure relates to use of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of, a microbial infection in a human or animal.

In another aspect, the present disclosure relates to a compound for usein the manufacture of a medicament for treating a microbial infection ina subject, wherein the compound is selected from a compound of thepresent disclosure, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer.

In some embodiments, the present disclosure relates to a compound foruse in the manufacture of a medicament for preventing a microbialinfection in a subject, wherein the compound is selected from a compoundof the present disclosure, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer.

In some embodiments, the present disclosure relates to a compound foruse in the manufacture of a medicament for reducing the risk of amicrobial infection in a subject, wherein the compound is selected froma compound of the present disclosure, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer.

In some embodiments, the present disclosure relates to a compound foruse in the manufacture of a medicament for delaying the onset of amicrobial infection in a subject, wherein the compound is selected froma compound of the present disclosure, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, for use in treating,preventing, reducing the risk of, or delaying the onset of a microbialinfection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, for use in treating amicrobial infection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, for use in preventing amicrobial infection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, for use in reducing therisk of a microbial infection in a human or animal.

In some embodiments, the present disclosure relates to a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, for use in delaying theonset of a microbial infection in a human or animal.

In some embodiments, a microbial infection as described herein is causedby one or more microoganisms selected from the group consisting of:Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae,Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species,and Escherichia coli. This group of microoganisms can be referred togenerally as the ESKAPE pathogens. In some embodiments, the microbialinfection is caused by a microorganism which is resistant to at leastone antibacterial. For example, the microorganism can be classified asmulti-drug resistant or extremely-drug resistant. In some embodiments,the compounds provided herein have in vitro activity across the ESKAPEpathogens. For example, one or more of the compounds provided hereinexhibit individual MICs and/or MIC90s of ≤4 mg/L. In some embodiments,one or more of the compounds provided herein exhibit individual MICsand/or MIC90s of ≤2 mg/L. For example, one or more of the compoundsprovided herein exhibit individual MICs and/or MIC90s of ≤1 mg/L. Insome embodiments, one or more of the compounds provided herein exhibitindividual MICs and/or MIC90s of ≤0.5 mg/L. For example, one or more ofthe compounds provided herein exhibit individual MICs and/or MIC90s of≤0.25 mg/L. In some embodiments, one or more of the compounds providedherein exhibit individual MICs and/or MIC90s of ≤0.125 mg/L. Forexample, one or more of the compounds provided herein exhibit individualMICs and/or MIC90s of ≤0.05 mg/L.

In some embodiments, the compounds provided herein lack cross-resistanceto current therapies, with demonstrated activity against one or moremultidrug-resistant strains of E. faecium and MRSA; Enterobacteriaceaefeaturing cephalosporinases (ESBLs and AmpCs) and carbapenemases(classes A, B and D); P. aeruginosa strains with normal and raisedefflux; and A. baumannii. In some embodiments, the compounds providedherein demonstrate one or more of low rate (E-10) and extent ofresistance development in E. coli; activity in exemplary burden modelsof infection in the neutropenic thigh, ascending kidney and lung as wellas in peritonitis models; and safety scorecard highlighted by 14-daydose-range-finding toxicology studies in rat and monkey, at multiplesthe exposures observed for efficacy, with minimal histopathologicalfindings.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of the compound or tautomer,wherein the microbial infection is caused by one or more of thefollowing microorganisms: Acinetobacter spp. (Acinetobacter baumanni),Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovatus,Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroidesvulgatus, Citrobacter freundii, Citrobacter koser, Chlamydiatrachomatis, Chlamydia psittaci, Chlamydia pneumoniae, Chlamydiapecorum, Chlamydia suis, Chlaymdia muridarum, Chlamydophila psittaci,Chlamydophila pneumoniae, Chlamydophila pecorum, Clostridioides spp.(e.g., Clostridioides difficile and Clostridioides mangenotii),Clostridium clostridioforme, Clostridium perfringens, Enterobacteraerogenes, Enterobacter cloacae, Enterococcus faecalis, Enterococcusspp. (vancomycin susceptible and resistant isolates), Escherichia coli(including ESBL and KPC producing isolates), Eubacterium lentum,Fusobacterium spp., Haemophilus influenzae (including beta-lactamasepositive isolates), Haemophilus parainfluenzae, Klebsiella pneumoniae(including ESBL and KPC producing isolates), Klebsiella oxytoca(including ESBL and KPC producing isolates), Legionella pneumophiliaMoraxella catarrhalis, Morganella morganii, Mycoplasma spp., Neisseriagonorrhoeae (including Neisseria gonorrhoeae ATCC49266, Neisseriagonorrhoeae 255123, Neisseria gonorrhoeae 255124, Neisseria gonorrhoeae255125, Neisseria gonorrhoeae 255126, Neisseria gonorrhoeae 255127,Neisseria gonorrhoeae J9104300210, Neisseria gonorrhoeae J9107400107,Neisseria gonorrhoeae J9109510210, Neisseria gonorrhoeae J9108110210),Peptostreptococcus spp., Porphyromonas asaccharolytica, Prevotellabivia, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri,Providencia stuartii, Pseudomonas aeruginosa, Salmonella enteritidis,Serratia marcescens, Streptococcus anginosus, Staphylococcus aureus(methicillin susceptible and resistant isolates), Staphylococcusepidermidis (methicillin susceptible and resistant isolates),Stenotrophomonas maltophilia, Streptococcus agalactiae, Streptococcusconstellatus, Streptococcus pneumoniae (penicillin susceptible andresistant isolates), Streptococcus pyogenes, or Streptococcus pyogenes.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of the compound or tautomer,wherein the infection is caused by or involves one or moremicroorganisms selected from: Acinetobacter spp. (Acinetobacterbaumanni), Bacteroides distasonis, Bacteroides fragilis, Bacteroidesovatus, Bacteroides thetaiotaomicron, Bacteroides unformis, Bacteroidesvulgatus, Citrobacter freundii, Citrobacter koser, Chlamydiatrachomatis, Chlamydia psittaci, Chlamydia pneumoniae, Chlamydiapecorum, hlamydia suis, Chlaymdia muridarum, Chlamydophila psittaci,Chlamydophila pneumoniae, Chlamydophila pecorum, Clostridioides spp.(e.g., Clostridioides difficile and Clostridioides mangenotii),Clostridium clostridioforme, Clostridium perfringens, Enterobacteraerogenes, Enterobacter cloacae, Enterococcus faecalis, Enterococcusspp., Escherichia coli, Eubacterium lentum, Fusobacterium spp.,Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiellapneumoniae, Klebsiella oxytoca, Legionella pneumophilia, Moraxellacatarrhalis, Morganella morganii, Mycoplasma spp., Neisseriagonorrhoeae, Peptostreptococcus spp., Porphyromonas asaccharolytica,Prevotella bivia, Proteus mirabilis, Proteus vulgaris, Providenciarettgeri, Providencia stuartii, Pseudomonas aeruginosa, Salmonellaenteritidis, Serratia marcescens, Streptococcus anginosus,Staphylococcus aureus, Staphylococcus epidermidis, Stenotrophomonasmaltophilia, Streptococcus agalactiae, Streptococcus constellatus,Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcuspyogenes.

In some embodiments, the present disclosure relates to a method whereinthe infection is caused by or involves one or more of aerobic andfacultative gram-positive microorganisms selected from: Staphylococcusaureus, Streptococcus pneumoniae, Enterococcus spp., Streptococcusagalactiae, Streptococcus pyogenes, and Staphylococcus epidermidis.

In some embodiments, the present disclosure relates to a method whereinthe infection is caused by or involves one or more of aerobic andfacultative gram-negative microorganisms selected from: Escherichiacoli, Haemophilus influenzae, Klebsiella pneumoniae, Citrobacterfreundii, Chlamydia trachomatis, Chlamydia psittaci, Chlamydiapneumoniae, Chlamydia pecorum, hlamydia suis, Chlaymdia muridarum,Chlamydophila psittaci, Chlamydophila pneumoniae, Chlamydophila pecorum,Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii,Neisseria gonorrhoeae, Salmonella enteritidis, Serratia marcescens,Pseudomonas aeruginosa, Acinetobacter baumanni, Moraxella catarrhalis,Proteus mirabilis, Citrobacter koseri, Haemophilus parainfluenzae,Klebsiella oxytoca, Proteus vulgaris, Providencia rettgeri, andProvidencia stuarti.

In some embodiments, the present disclosure relates to a method whereinthe infection is caused by or involves one or more anaerobicmicroorganisms: Bacteroides fragilis, Bacteroides distasonis,Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis,Clostridioides spp. (e.g., Clostridioides difficile and Clostridioidesmangenotii), Clostridium clostridioforme, Eubacterium lentum,Peptostreptococcus spp., Porphyromonas asaccharolytica, Prevotellabivia, Bacteroides vulgatus, Clostridium perfringens, and Fusobacteriumspp.

In some embodiments, the present disclosure relates to a method, whereinthe microorganism Enterococcus spp. is selected from vancomycinsusceptible isolate and vancomycin resistant isolate. For example,vancomycin-resistant Enterococci.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Escherichia coli is selected from extended spectrumbeta-lactamase (ESBL) producing isolate and Klebsiella pneumoniaecarbapenemase (KPC) producing isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Haemophilus influenzae is a beta-lactamase positiveisolate.

In some embodiments, the present disclosure relates to a method wherein,the microorganism Klebsiella pneumoniae is selected from extendedspectrum beta-lactamase (ESBL) producing isolate and Klebsiellapneumoniae carbapenemase (KPC) producing isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Klebsiella oxytoca selected from extended spectrumbeta-lactamase (ESBL) producing isolate and Klebsiella pneumoniaecarbapenemase (KPC) producing isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Staphylococcus aureus is selected from methicillinsusceptible isolate and methicillin resistant isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Staphylococcus epidermidis is selected frommethicillin susceptible isolate and methicillin resistant isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Streptococcuspneumoniae is selected from penicillinsusceptible isolate and penicillin resistant isolate.

In some embodiments, the present disclosure relates to a method whereinthe microorganism Neisseria gonorrhoeae is selected from susceptible andresistant isolates, including, for example, ceftriaxone-resistant,ciprofloxacin-resistant and azithromycin-resistant isolates.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of the compound or tautomer,wherein the microbial infection is caused by or involves one or moremicroorganisms which are capable of being used as biological weapons,e.g., wherein the one or more microorganisms are selected from Bacillusanthracis and Multi Drug Resistant (MDR) anthracis, Franciscellatularensis, Yersinia pestis, Burkholderia mallei, and Burkholderiapseudomallei.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound or a tautomer thereof,or a pharmaceutically acceptable salt of the compound or tautomer,wherein the microbial infection is caused by one or more of thefollowing microorganisms: Bacillus anthracis and Multi Drug Resistant(MDR) anthracis, Franciscella tularensis, Yersinia pestis, Burkholderiamallei, and Burkholderia pseudomallei.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal comprising administering to thehuman or animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer, or use of a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of the compound ortautomer, in the manufacture of a medicament for treating, preventing,reducing the risk of, or delaying the onset of a microbial infection ina human or animal, wherein the microbial infection is selected from thegroup consisting of: a skin infection, a Gram positive infection, a Gramnegative infection, nosocomial pneumonia, community acquired pneumonia,post-viral pneumonia, hospital acquired pneumonia/ventilator associatedpneumonia, a respiratory tract infection such as chronic respiratorytract infection (CRTI), acute pelvic infection, a complicated skin andskin structure infection, a skin and soft tissue infection (SSTI)including uncomplicated skin and soft tissue infections (uSSTI)s andcomplicated skin and soft tissue infections, an abdominal infection, acomplicated intra-abdominal infection, a urinary tract infection,bacteremia, septicemia, endocarditis, an atrio-ventricular shuntinfection, a vascular access infection, meningitis, surgicalprophylaxis, a peritoneal infection, a bone infection, a jointinfection, a methicillin-resistant Staphylococcus aureus infection, avancomycin-resistant Enterococci infection, a ciprofloxacin-resistantNeisseria gonorrhoeae infection, a carbapenem-resistantEnterobacteriaceae infection, a linezolid-resistant organism infection,gonorrhea, chlamydia, and tuberculosis.

The compounds of the present disclosure can be used, for example for thetreatment of patients with moderate to severe infections, which may becaused by susceptible isolates of the indicated microorganisms.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acomplicated intra-abdominal infection in a human or animal comprisingadministering to the human or animal an effective amount of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, or to the use of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of a complicated intra-abdominal infection in a human oranimal.

In some embodiments, the complicated intra-abdominal infection isselected from polymicrobial infections such as abscess due toEscherichia coli, Clostridium clostridioforme, Eubacterium lentum,Peptostreptococcus spp., Bacteroides fragilis, Bacteroides distasonis,Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides unformis,Streptococcus anginosus, Streptococcus constellatus, Enterococcusfaecalis, Proteus mirabilis, or Clostridium perfringens.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acomplicated skin and skin structure infection (cSSSI, also known asacute bacterial skin and skin structure infections or ABSSSI) in a humanor animal comprising administering to the human or animal an effectiveamount of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer, or to theuse of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of a complicated skin and skin structureinfection.

In some embodiments, the complicated skin and skin structure infectionis selected from diabetic foot infections without osteomyelitis due toStaphylococcus aureus (methicillin susceptible and resistant isolates),Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coi,Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis,Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotellabivia.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acommunity acquired pneumonia (CAP) in a human or animal comprisingadministering to the human or animal an effective amount of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, or to the use of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of community acquired pneumonia.

In some embodiment, the community acquired pneumonia is due toStreptococcus pneumoniae (penicillin susceptible and resistant isolates)including cases with concurrent bacteremia, Haemophilus influenzae(including beta-lactamase positive isolates), Moraxella catarrhalis, oratypical bacteria like Mycoplasma spp.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of acomplicated urinary tract infection (cUTI) in a human or animalcomprising administering to the human or animal an effective amount of acompound disclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, or to the use of a compounddisclosed herein, or a tautomer thereof, or a pharmaceuticallyacceptable salt of the compound or tautomer, in the manufacture of amedicament for treating, preventing, reducing the risk of, or delayingthe onset of a complicated urinary tract infection.

In some embodiment, the complicated urinary tract infection is selectedfrom pyelonephritis due to Escherichia coli, concurrent bacteremia, orKlebsiella pneumoniae.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of anacute pelvic infection in a human or animal comprising administering tothe human or animal an effective amount of a compound disclosed herein,or a tautomer thereof, or a pharmaceutically acceptable salt of thecompound or tautomer, or to the use of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer, in the manufacture of a medicament for treating,preventing, reducing the risk of, or delaying the onset of an acutepelvic infection.

In some embodiments, the acute pelvic infection is selected frompostpartum endomyometritis, septic abortion and post-surgicalgynecologic infections and the infection is due to a microorganismselected from Streptococcus agalactiae, Escherichia coli, Bacteroidesfragilis, Porphyromonas asaccharolytica, Peptostreptococcus spp., andPrevotella bivia.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of ahospital acquired pneumonia (HAP)/ventilator associated pneumonia (VAP)in a human or animal comprising administering to the human or animal aneffective amount of a compound disclosed herein, or a tautomer thereof,or a pharmaceutically acceptable salt of the compound or tautomer, or tothe use of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of hospital acquired pneumonia/ventilatorassociated pneumonia.

In some embodiments, the hospital acquired pneumonia/ventilatorassociated pneumonia is due to a microorganism selected fromStreptococcus pneumoniae (penicillin susceptible and resistantisolates), Staphylococcus aureus (methicillin susceptible and resistantisolates), Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacterspp., Stenotrophomonas maltophilia, Haemophilus influenzae (includingbeta-lactamase positive isolates), and Legionella pneumophilia.

The compounds or tautomers or pharmaceutically acceptable salts of thecompounds or tautomers of the present disclosure may also be useful forthe prevention, prophylaxis, or reduction of surgical site infections.In some embodiments, the compounds or tautomers or pharmaceuticallyacceptable salts of the compounds or tautomers of the present disclosureare useful following elective colorectal surgery.

Appropriate specimens for bacteriological examination should be obtainedin order to isolate and identify the causative organisms and todetermine their susceptibility to the compounds of the presentdisclosure. Therapy with the compounds or tautomers or pharmaceuticallyacceptable salts of the compounds or tautomers of the present disclosuremay be initiated empirically before results of these tests are known;once results become available, antimicrobial therapy should be adjustedaccordingly.

To reduce the development of drug-resistant bacteria and maintain theeffectiveness of the compounds or tautomers or pharmaceuticallyacceptable salts of the compounds or tautomers of the present disclosureand other antibacterial drugs, the compounds or tautomers orpharmaceutically acceptable salts of the compounds or tautomers shouldbe used only to treat or prevent infections that are proven or stronglysuspected to be caused by susceptible bacteria. When culture andsusceptibility information are available, they should be considered inselecting or modifying antibacterial therapy. In the absence of suchdata, local epidemiology and susceptibility patterns may contribute tothe empiric selection of therapy.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection due to an aerobic or facultative gram-positivemicroorganism in a human or animal comprising administering to the humanor animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer, or to the use of a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of the compound ortautomer, in the manufacture of a medicament for treating, preventing,reducing the risk of, or delaying the onset of a microbial infection dueto an aerobic or facultative gram-positive microorganism.

In some embodiments, the aerobic or facultative gram-positivemicroorganism is selected from: Staphylococcus aureus (methicillinsusceptible and resistant isolates), Streptococcus pneumoniae(penicillin susceptible and resistant isolates), Enterococcus spp.(vancomycin susceptible and resistant isolates), Streptococcusagalactiae, Streptococcus pyogenes, and Staphylococcus epidermidis(methicillin susceptible and resistant isolates).

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection due to an aerobic and facultative gram-negativemicroorganism in a human or animal comprising administering to the humanor animal an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer, or to the use of a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of the compound ortautomer, in the manufacture of a medicament for treating, preventing,reducing the risk of, or delaying the onset of a microbial infection dueto an aerobic or facultative gram-positive microorganism.

In some embodiments, the aerobic and facultative gram-negativemicroorganism is selected from: Escherichia coli [including extendedspectrum beta-lactamase (ESBL) and Klebsiella pneumoniae (KPC) producingisolates), Haemophilus influenzae (including Beta-lactamase positiveisolates), Klebsiella pneumoniae (including ESBL and KPC producingisolates), Citrobacter freundii, Enterobacter aerogenes, Enterobactercloacae, Morganella morganii, Salmonella enteritidis, Serratiamarcescens, Pseudomonas aeruginosa, Acinetobacter baumanni, Moraxellacatarrhalis, Proteus mirabilis, Citrobacter koseri, Haemophilusparainfluenzae, Klebsiella oxytoca (including ESBL and KPC producingisolates), Proteus vulgaris, Providencia rettgeri, and Providenciastuartii.

In some embodiments, the present disclosure relates to a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection due to an anaerobic microorganism in a human oranimal comprising administering to the human or animal an effectiveamount of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer, or to theuse of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of a microbial infection due to an anaerobicmicroorganism.

In some embodiments, the anaerobic microorganism is selected from:Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus,Bacteroides thetaiotaomicron, Bacteroides uniformis, Clostridioides spp.(e.g., Clostridioides difficile and Clostridioides mangenotii),Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcusspecies, Porphyromonas asaccharolytica, Prevotella bivia, Bacteroidesvulgates, Clostridium perfringens, and Fusobacterium spp.

In some embodiments, the present disclosure relates to a method oftreating or reducing the risk of a microbial infection in a human oranimal comprising administering to the human or animal an effectiveamount of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer, or to theuse of a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer, in themanufacture of a medicament for treating, preventing, reducing the riskof, or delaying the onset of a microbial infection.

In some embodiments, the microorganism is Legionella pneumophilia.

In some embodiments, the microorganism Enterococcus spp. is selectedfrom vancomycin susceptible isolate and vancomycin resistant isolate. Insome embodiments, the microorganism Escherichia coli is selected fromextended spectrum beta-lactamase (ESBL) producing isolate and Klebsiellapneumoniae carbapenemase (KPC) producing isolate. In some embodiments,the microorganism Haemophilus influenzae is a beta-lactamase positiveisolate. In some embodiments, the microorganism Klebsiella pneumoniae isselected from extended spectrum beta-lactamase (ESBL) producing isolateand Klebsiella pneumoniae carbapenemase (KPC) producing isolate. In someembodiments, the microorganism Klebsiella oxytoca selected from extendedspectrum beta-lactamase (ESBL) producing isolate and Klebsiellapneumoniae carbapenemase (KPC) producing isolate. In some embodiments,the microorganism Staphylococcus aureus is selected from methicillinsusceptible isolate and methicillin resistant isolate. In someembodiments, the microorganism Staphylococcus epidermidis is selectedfrom methicillin susceptible isolate and methicillin resistant isolate.In some embodiments, the microorganism Streptococcus pneumoniae isselected from penicillin susceptible isolate and penicillin resistantisolate.

In some embodiments, the microorganism is colistin-resistant. Forexample, a microorganism that is colistin-resistant exhibits a minimuminhibitory concentration (MIC) for colistin of >2 g/ml). In someembodiments, the microorganism is be a gram negative bacteria such as aPseudomonas (e.g., Pseudomonas aeruginosa), Escherichia (Escherichiacoli), Acinetobacter (e.g., Acinetobacter baumannii), or Klebsiella(e.g., Klebsiella pneumoniae) species that is resistant to treatmentwith the antibacterial agent known as colistin (polymyxin E). Forexample, the colistin-resistant microorganism is selected fromPseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacterbaumannii. In some embodiments, the colistin-resistant microorganism isa Stenotrophomonas, Burkholderia, Proteus, Serratia, Morganella, orProvidencia species (e.g., the specific species provided herein).

In some embodiments, the microorganism is ceftazidime-resistant. Forexample, a microorganism that is ceftazidime-resistant exhibits aminimum inhibitory concentration (MIC) for ceftazidime of >2 g/ml). Insome embodiments, the microorganism is be a gram negative bacteria suchas a Pseudomonas (e.g., Pseudomonas aeruginosa), Escherichia(Escherichia col), or Klebsiella (e.g., Klebsiella pneumoniae) speciesthat is resistant to treatment with the antibacterial agent known asceftazidime (Fortraz). For example, the ceftazidime-resistantmicroorganism is selected from Pseudomonas aeruginosa, Klebsiellapneumoniae, and Escherichia coli. In some embodiments, the microorganismis gentamicin-resistant. For example, a microorganism that isgentamicin-resistant exhibits a minimum inhibitory concentration (MIC)for gentamicin of >2 g/ml). In some embodiments, the microorganism isselected from Pseudomonas (e.g., Pseudomonas aeruginosa), Escherichia(Escherichia coli), Acinetobacter (e.g., Acinetobacter baumannii orAcinetobacter calcoaceticus var. anitratum), Proteus (e.g., Proteusmirabilis or Proteus vulgaris), Enterobacter (Enterobacter aerogenes orEnterobacter cloacae), Staphylococcus (e.g., Staphylococcus aureus orStaphylococcus epidermidis) or Klebsiella (e.g., Klebsiella pneumoniae)species that is resistant to treatment with the antibacterial agentknown as gentamicin (Garamycin). In some embodiments, the microorganismis a gram negative bacteria species that is resistant to treatment withthe antibacterial agent known as gentamicin.

In some embodiments, the microorganism is levofloxacin-resistant. Forexample, a microorganism that is levofloxacin-resistant exhibits aminimum inhibitory concentration (MIC) for colistin of >2 g/ml). In someembodiments, the microorganism is selected from Escherichia (Escherichiacoli), or Streptococcus (Streptococcus pneumoniae, Streptococcusagalactiae, or Streptococcus pyogenes) species that is resistant totreatment with the antibacterial agent known as levofloxacin (Levaquin).In some embodiments, the microorganism is a gram negative bacteria thatis resistant to treatment with the antibacterial agent known aslevofloxacin (Levaquin).

In some embodiments, the microorganism is carbapenem-resistant. Forexample, a microorganism that is carbapenem-resistant exhibits a minimuminhibitory concentration (MIC) for carbapenem of >2 g/ml). In someembodiments, the microorganism is be a selected from a Escherichia(Escherichia col), Enterobacter (Enterobacter aerogenes or Enterobactercloacae), or Klebsiella (e.g., Klebsiella pneumoniae) species that isresistant to treatment with the antibacterial agent from the class knownas carbapenems.

For example, the carbapemen-resistant microorganism is selected fromEscherichia coli, Enterobacter aerogenes, Enterobacter cloacae complex,Klebsiella pneumoniae, or Klebsiella oxytoca that is resistant totreatment with the antibacterial agent from the class known ascarbapenems. In some embodiments, the microorganism is a gram negativebacteria that is resistant to treatment with the antibacterial agentfrom the class known as carbapenems.

In some embodiments, a method or use disclosed herein is a method or useto treat a subject that would be subjected to a surgical or invasivemedical procedure. Such a subject can be considered to be in need of themethods of treating, reducing the risk of or preventing the infectiondue to a surgical procedure or an invasive medical procedure. Such asubject can also be considered to be in need of peri-operativeprophylaxis.

In some embodiments, a method or use provided herein is a method fortreating sepsis in a subject comprising administering to the subject atherapeutically effective amount of a compound or a tautomer thereof, ora pharmaceutically acceptable salt of the compound of tautomer thereof.In some such embodiments, the patient is a pediatric patient, ageriatric patient, or a patient having a weakened immune system relatedto another disease or disorder (e.g., cancer, diabetes, major trauma, orburns). In some embodiments, the sepsis is severe sepsis. In someembodiments, the sepsis is septic shock. In some embodiments, thetreatment of sepsis further comprises administration to the subject oneor more of intravenous fluids, compounds capable of raising bloodpressure, mechanical ventilation, and dialysis.

In some embodiments, the present disclosure provides a method oftreating, preventing, reducing the risk of, or delaying the onset of amicrobial infection in a human or animal, the method includingadministering to the human or animal in need thereof an effective amountof a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer. In someembodiments, the infection is caused by or involves one or moremicroorganisms which are capable of being used as biological weapons. Insome embodiments, the infection is caused by or involves one or moremicroorganisms which are extremely-drug resistant Gram-positive orGram-negative pathogens.

In some embodiments, provided is the use of one or more compoundsdisclosed herein, including stereoisomers, tautomers, and salts thereof,in the manufacture of a medicament for treating, preventing, reducingthe risk of, or delaying the onset of a microbial infection in a humanor animal. In some embodiments, the infection is caused by or involvesone or more microorganisms which are capable of being used as biologicalweapons. In some embodiments, the infection is caused by or involves oneor more microorganisms which are extremely-drug resistant Gram-positiveor Gram-negative pathogens.

In some embodiments, provided are one or more compounds disclosedherein, including stereoisomers, tautomers, and salts thereof, for usein treating, preventing, reducing the risk of, or delaying the onset ofa microbial infection in a human or animal. In some embodiments, theinfection is caused by or involves one or more microorganisms which arecapable of being used as biological weapons. In some embodiments, theinfection is caused by or involves one or more microorganisms which areextremely-drug resistant Gram-positive or Gram-negative pathogens.

In one embodiment, provided is a method of treating a microbialinfection in a subject, that includes administering to the subject aneffective amount of one or more compounds of a compound disclosedherein, or a tautomer thereof, or a pharmaceutically acceptable salt ofthe compound or tautomer, where the infection is caused by or involvesone or more microorganisms which are capable of being used as biologicalweapons. In some embodiments, the infection is caused by or involves oneor more microorganisms which are capable of being used as biologicalweapons. In some embodiments, the infection is caused by or involves oneor more microorganisms which are extremely-drug resistant Gram-positiveor Gram-negative pathogens.

In one embodiment, provided is a method of preventing a microbialinfection in a subject, that includes administering to the subject aneffective amount of a compound disclosed herein, or a tautomer thereof,or a pharmaceutically acceptable salt of the compound or tautomer, wherethe infection is caused by or involves one or more microorganisms whichare capable of being used as biological weapons. In some embodiments,the infection is caused by or involves one or more microorganisms whichare capable of being used as biological weapons. In some embodiments,the infection is caused by or involves one or more microorganisms whichare extremely-drug resistant Gram-positive or Gram-negative pathogens.

In one embodiment, provided is a method of reducing the risk of amicrobial infection in a subject, that includes administering to thesubject an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer, where the infection is caused by or involves one or moremicroorganisms which are capable of being used as biological weapons. Insome embodiments, the infection is caused by or involves one or moremicroorganisms which are capable of being used as biological weapons. Insome embodiments, the infection is caused by or involves one or moremicroorganisms which are extremely-drug resistant Gram-positive orGram-negative pathogens.

In one embodiment, provided is a method of delaying the onset of amicrobial infection in a subject, that includes administering to thesubject an effective amount of a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer, where the infection is caused by or involves one or moremicroorganisms which are capable of being used as biological weapons. Insome embodiments, the infection is caused by or involves one or moremicroorganisms which are capable of being used as biological weapons. Insome embodiments, the infection is caused by or involves one or moremicroorganisms which are extremely-drug resistant Gram-positive orGram-negative pathogens.

In some embodiments, a bacterium which can be used as a biologicalweapon possesses one or more characteristics that include, but are notlimited to, being easily being produced or disseminated, being easilytransmitted from person to person, having the potential for moderate orhigh morbidity, having the potential for moderate or high mortality,having the potential for causing public panic and social disruption,requiring special action for public health preparedness, and requiringspecific enhancements for diagnosis and disease surveillance.

In another embodiment, a bacterium which can be used as a biologicalweapon is stable or viable, for example, the bacterium is capable ofperforming all or part of its normal biological functions, such asreplicating, forming spores, and infecting a subject, under variousconditions. In some embodiments, the bacterium is stable or viable inone or more conditions that include, but are not limited to, heat, cold,high pressure, low pressure, acidic or basic conditions, humidity,dryness, and radiation, including extreme conditions.

In one embodiment, a bacterium which can be used as a biological weaponis stable or viable at a temperature above about 25° C., such as aboveabout 30° C., about 40° C., about 50° C., about 60° C., about 70° C.,about 80° C., about 90° C., about 100° C., about 125° C., about 150° C.,about 175° C., or above about 200° C. In another embodiment, a bacteriumwhich can be used as a biological weapon is stable or viable at atemperature below about 25° C., such as below about 20° C., about 10°C., about 5° C., about 0° C., about −10° C., about −20° C., about −30°C., about −40° C., about −50° C., about −60° C., about −70° C., about−100° C., or below about −150° C.

In one embodiment, a bacterium which can be used as a biological weaponis capable of infecting a subject under various conditions, such asvarious pressures. In one embodiment, a bacterium which can be used as abiological weapon is stable or viable under pressure above about 5×10⁵Pa, such as above about 10×10⁵ Pa, about 15×10⁵ Pa, about 20×10⁵ Pa,about 30×10⁵ Pa, about 40×10⁵ Pa, about 50×10⁵ Pa, about 75×10⁵ Pa, orabout 100×10⁵ Pa. In another embodiment, a bacterium which can be usedas a biological weapon is stable or viable under pressure below about0.5×10⁵ Pa, such as below about 0.2×10⁵ Pa, about 0.1×10⁵ Pa, about0.05×10⁵ Pa, about 0.02×10⁵ Pa, about 0.01×10⁵ Pa, about 0.005×10⁵ Pa,about 0.002×10⁵ Pa, or about 0.001×10⁵ Pa.

In one embodiment, a bacterium which can be used as a biological weaponis stable or viable at a pH above about 8.0, such as above about 8.5,about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5,about 12.0, about 12.5, about 13.0, about 13.5, or about 14.0. Inanother embodiment, a bacterium which can be used as a biological weaponis stable or viable at a pH below about 6.0, such as below about 5.5,about 5.0, about 4.5, about 4.0, about 3.5, about 3.0, about 2.5, about2.0, about 1.5, about 1.0, about 0.5, or about 0.0.

In one embodiment, a bacterium which can be used as a biological weaponis stable or viable under a relative humidity of about 10%, such asabout 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, or about 99%.

In another embodiment, a bacterium which can be used as a biologicalweapon is stable or viable under UV radiation, X-ray radiation, aradiation, p radiation, or y radiation.

In one embodiment, a bacterium which can be used as a biological weaponis able to form spores.

In some embodiments, a bacterium which can be used as a biologicalweapon can be dispersed in air or in liquid. In one embodiment, thebacterium is in aeorosol form, for example, the bacterium is formulatedas an aerosol. In another embodiment, the bacterium is in powder form,for example, the bacterium is formulated as powder.

In one embodiment, a bacterium which can be used as a biological weaponincludes a bacterium which is resistant to existing antibiotics. In someembodiments, the bacterium is resistant to tetracycline antibiotics,including, but not limited to, tetracycline, doxycycline, minocycline,sancycline, methacycline, chlortetracycline, and deoxytetracycline, anda combination thereof. In some embodiments, the bacterium is resistantto other antibiotics, including, but not limited to, aminoglycosides,such as gentamicin and kanamycin, colistin, methicillin, oxacillin,vancomycin, penicillin, linezolid, fluoroquinolones, such asciprofloxacin, ceftazidime, and macrolides, such as azithromycin. Insome embodiments, a bacterium which can be used as a biological weaponincludes a bacterium which is resistant to gentamicin. In someembodiments, a bacterium which can be used as a biological weaponincludes a bacterium which is resistant to colistin. In someembodiments, a bacterium which can be used as a biological weaponincludes a bacterium which is resistant to gentamicin and colistin.

In some embodiments of the disclosed methods, the one or moremicroorganisms are biodefense category A or biodefense category Bpathogens. Biodefense category A pathogens are those organisms orbiological agents that pose the highest risk to national security andpublic health because they (1) can be easily disseminated or transmittedfrom person to person, (2) result in high mortality rates and have thepotential for major public health impact, (3) might cause public panicand social disruption, and (4) require special action for public healthpreparedness. Examples of category A pathogens include, but are notlimited to, Bacillus anthracis (anthrax), Francisella tularensis(tularemia), Yersinia pestis (plague), Ebola, Marburg, Ebola-likeviruses such as Bundibugyo ebolavirus, Sudan ebolavirus, TaiForestebolavirus, Zaire ebolavirus and Marburg-like viruses such as Marburgvirus and Ravn virus. In some embodiments, the one or moremicroorganisms are selected from the group consisting of biodefensecategory A pathogens Bacillus anthracis (anthrax), Yersinia pestis(plague), and Francisella tularensis (tularemia).

Biodefense category B pathogens are the second highest priorityorganisms or biological agents. They are moderately easy to disseminate,result in moderate morbidity rates and low mortality rates, and requirespecific enhancements for diagnostic capacity and enhanced diseasesurveillance. Examples of category B pathogens include, but are notlimited to, Burkholderia pseudomallei (melioidosis), Coxiella burnetii(Q fever), Brucella species (brucellosis), Burkhoderia mallei(glanders), Chlamydia psittaci (psittacosis), Rickettsia prowazekii(typhus fever), diarrheagenic E. coli, pathogenic Vibrios, Shigellaspecies, Salmonella, Listeria monocytogenes, Campylobacter jejuni,Yersinia enterocolitica, Staphylococcus enterotoxin B, and Hepatitis A.In some embodiments, the one or more microorganisms are selected fromthe group consisting of biodefense category B pathogens Burkholderiapseudomallei (melioidosis), Coxiella burnetii (Q fever), Brucellaspecies (brucellosis), Burkhoderia mallei (glanders), Chlamydia psittaci(psittacosis), Rickettsia prowazekii (typhus fever), diarrheagenic E.coli, pathogenic Vibrios, Shigella species, Salmonella, Listeriamonocytogenes, Campylobacter jejuni, and Yersinia enterocolitica.

More examples of category A or B pathogens are provided by the NationalInstitute of Allergy and Infectious Diseases (NIAID) at http://www.niaid.nih.gov/topics/bi odefenserelated/bi odefense/pages/cata.aspx#, thecontents of which are hereby incorporated by reference in its entirety.

In some embodiments, a bacterium which can be used as a biologicalweapon includes, but is not limited to, a bacterium of the Bacilluscereus group. The Bacillus cereus group of bacteria includes Bacillusanthracis (the etiologic agent of anthrax), Bacillus cereus, Bacillusweihenstephanensis (a food borne pathogen), Bacillus thuringiensis (aninsect pathogen), and Bacillus mycoides. In some embodiments, thebacterium is selected from Bacillus anthracis, multidrug-resistant (MDR)anthrax, Francisella tularensis, Clostridium botulinum, Yersinia pestis,Burkholderia mallei, Burkholderia pseudomallei, Brucella species,Shigella species, Coxiella burnetii, Chlamydia psittaci, Clostridiumperfringens, Rickettsia prowazekii, diarrheagenic E. coli, pathogenicVibrios, Salmonella, Campylobacter jejuni, Yersinia enterocolitica, andListeria monocytogenes. In some embodiments, the microorganism(bacterium) is selected from Bacillus anthracis, Franciscellatularensis, Yersinia pestis, Burkholderia mallei, and Burkholderiapseudomallei. In some embodiments, the microorganism (bacterium) isselected from Burkholderia mallei and Burkholderia pseudomallei. In someembodiments, the microorganism (bacterium) is Burkholderia pseudomallei.

In some embodiments, a bacterium which can be used as a biologicalweapon is Bacillus anthracis or multidrug-resistant (MDR) anthrax.

In some embodiments, a bacterium which can be used as a biologicalweapon is Burkholderia pseudomallei.

In some embodiments, a bacterium which can be used as a biologicalweapon includes, but is not limited to, gram-positive pathogens,gram-negative pathogens, anaerobic pathogens, or atypical pathogens, ora combination thereof. In some embodiments, the bacterium includesmethicillin-susceptible Staphylococcus aureus (MSSA),methicillin-resistant Staphylococcus aureus (MRSA),oxacillin-susceptible Staphylococcus aureus, oxacillin-resistantStaphylococcus aureus, oxacillin-resistant coagulase-negativeStaphylococcus, Enterococcus faecalis, Enterococcus faecium,vancomycin-susceptible Enterococcus faecium, vancomycin-resistantEnterococcus faecium, vancomycin-susceptible Enterococcus faecalis,vancomycin-resistant Enterococcus faecalis, Streptococcus pneumoniae,penicillin-susceptible Streptococcus pneumonia, penicillin-resistantStreptococcus pneumoniae (PRSP), Streptococcus pyogenes, Streptococcusagalactiae, Haemophilus influenzae, Moraxella catarrhalis, Neisseriagonorrhoeae, Escherichia coli, Shigella spp., Salmonella spp.,Klebsiella pneumoniae, Enterobacter aerogenes, Enterobacter cloacae,Serratia marcescens, Acinetobacter baumannii, Stenotrophomonasmaltophilia, Bacteroides fragilis, Clostridium perfringens, Chlamydiapneumoniae, Legionella pneumophila, Proteus mirabilis, Pseudomonasaeruginosa, and Burkholderia cepacia.

In some embodiments, the one or more microorganisms are extremely-drugresistant Gram-positive or Gram-negative pathogens.

In some embodiments, provided is a method of treating, preventing,reducing the risk of, or delaying the onset of a microbial infection ina subject that is caused by or involves one or more microorganisms whichare capable of being used as biological weapons that includesadministering a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer.

In some embodiments, the one or more microorganisms are biodefensecategory A pathogens. In some embodiments, the one or moremicroorganisms are biodefense category A pathogens selected fromBacillus anthracis (anthrax), Yersiniapestis (plague), and Francisellatularensis (tularemia).

In some embodiments, the one or more microorganisms are biodefensecategory B pathogens. In some embodiments, the one or moremicroorganisms are biodefense category B pathogens Burkholderiapseudomallei (melioidosis), Coxiella burnetii (Q fever), Brucellaspecies (brucellosis), Burkhoderia mallei (glanders), Chlamydia psittaci(psittacosis), Rickettsia prowazekii (typhus fever), diarrheagenic E.coli, pathogenic Vibrios, Shigella species, Salmonella, Listeriamonocytogenes, Campylobacter jejuni, and Yersinia enterocolitica.

In some embodiments, the one or more microorganisms are selected fromBacillus anthracis, Franciscella tularensis, Yersinia pestis,Burkholderia mallei, and Burkholderia pseudomallei.

In some embodiments, the one or more microorganisms are selected fromBurkholderia mallei and Burkholderia pseudomallei. In some embodiments,the one or more microorganisms are Burkholderia pseudomallei.

In some embodiments, provided is a method of treating, preventing,reducing the risk of, or delaying the onset of a microbial infection ina subject that is caused by or involves one or more microorganisms whichare extremely-drug resistant Gram-positive or Gram-negative pathogensthat includes administering a compound disclosed herein, or a tautomerthereof, or a pharmaceutically acceptable salt of the compound ortautomer.

In some embodiments, provided is a method of treating a microbialinfection in a subject that includes administering a compound disclosedherein, or a tautomer thereof, or a pharmaceutically acceptable salt ofthe compound or tautomer, after the subject has been exposed to themicroorganism, but before the subject develops any symptom of themicrobial infection. In some embodiments, the microorganism is abacterium. In some embodiments, the microbial infection is a bacterialinfection. In some embodiments, a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer, is administered about 10 min, about 20 min, about 30 min,about 40 min, about 50 min, about 1 hr, about 2 hrs, about 3 hrs, about6 hrs, about 12 hrs, about 18 hrs, about 24 hrs, about 36 hrs, about 48hrs, about 72 hrs, about 96 hrs, about 1 week, or about 2 weeks afterthe subject has been exposed to the microorganism, but before thesubject develops any symptoms. In another embodiment, provided is amethod of treating a microbial infection in a subject that includesadministering a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer, after thesubject develops a symptom after the subject has been exposed to themicroorganism. In some embodiments, the microorganism is a bacterium. Inone embodiment, a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer, isadministered about 10 min, about 20 min, about 30 min, about 40 min,about 50 min, about 1 hr, about 2 hrs, about 3 hrs, about 6 hrs, about12 hrs, about 18 hrs, about 24 hrs, about 36 hrs, about 48 hrs, about 72hrs, about 96 hrs, about 1 week, or about 2 weeks after the subjectdevelops a symptom.

In another embodiment, provided is a method of treating a microbialinfection in a subject that includes administering a compound disclosedherein, or a tautomer thereof, or a pharmaceutically acceptable salt ofthe compound or tautomer, after the subject's suspected exposure to themicroorganism, but before the subject develops any symptom of themicrobial infection. In one embodiment, the compound disclosed herein,or a tautomer thereof, or a pharmaceutically acceptable salt of thecompound or tautomer, is administered about 10 min, about 20 min, about30 min, about 40 min, about 50 min, about 1 hr, about 2 hrs, about 3hrs, about 6 hrs, about 12 hrs, about 18 hrs, about 24 hrs, about 36hrs, about 48 hrs, about 72 hrs, about 96 hrs, about 1 week, or about 2weeks after the subject's suspected exposure to the microorganism, butbefore the subject develops any symptoms. In some embodiments, themicroorganism is a bacterium.

In some embodiments, provided is a method of preventing a microbialinfection in a subject that includes administering a compound disclosedherein, or a tautomer thereof, or a pharmaceutically acceptable salt ofthe compound or tautomer, before the subject has been exposed to themicroorganism. In some embodiments, the microorganism is a bacterium. Insome embodiments, the microbial infection is a bacterial infection. Insome embodiments, the compound disclosed herein, or a tautomer thereof,or a pharmaceutically acceptable salt of the compound or tautomer, isadministered about 10 min, about 20 min, about 30 min, about 40 min,about 50 min, about 1 hr, about 2 hrs, about 3 hrs, about 6 hrs, about12 hrs, about 18 hrs, about 24 hrs, about 36 hrs, about 48 hrs, about 72hrs, about 96 hrs, about 1 week, or about 2 weeks before the subject hasbeen exposed to the microorganism.

In another embodiment, provided is a method of preventing a microbialinfection in a subject that includes administering a compound disclosedherein, or a tautomer thereof, or a pharmaceutically acceptable salt ofthe compound or tautomer, before or after an event which raises the riskof the subject being exposed to the microorganism. In some embodiments,the microorganism is a bacterium. The event includes, but is not limitedto, an attack, for example, a terrorist attack, with a biological weaponand the subject's entry into a risky territory, such as a battlefield.In one embodiment, a compound disclosed herein, or a tautomer thereof,or a pharmaceutically acceptable salt of the compound or tautomer, isadministered to the subject about 10 min, about 20 min, about 30 min,about 40 min, about 50 min, about 1 hr, about 2 hrs, about 3 hrs, about6 hrs, about 12 hrs, about 18 hrs, about 24 hrs, about 36 hrs, about 48hrs, about 72 hrs, about 96 hrs, about 1 week, or about 2 weeks beforethe event. In another embodiment, a compound disclosed herein, or atautomer thereof, or a pharmaceutically acceptable salt of the compoundor tautomer is administered to the subject about 10 min, about 20 min,about 30 min, about 40 min, about 50 min, about 1 hr, about 2 hrs, about3 hrs, about 6 hrs, about 12 hrs, about 18 hrs, about 24 hrs, about 36hrs, about 48 hrs, about 72 hrs, about 96 hrs, about 1 week, or about 2weeks after the event.

In another embodiment, the method of the present disclosure includes,before administering a compound disclosed herein, or a tautomer thereof,or a pharmaceutically acceptable salt of the compound or tautomer,identifying a subject at risk of being exposed to a microorganism whichcan be used as a biological weapon. In some embodiments, themicroorganism is a bacterium. In some embodiments, the subject at riskof being exposed to a microorganism which can be used as a biologicalweapon includes, but is not limited to, a subject travelling to,entering, or being in a conflict region, for example, a battlefield orcombat zone, including military personnel, intelligence personnel, andanimals used in the military, a subject engaged or about to be engagedin a security operation, such as governmental authorities (for example,police, governmental investigators, and secret service members) andother personnel (for example, doctors, nurses, and rescue workers), andanimals used in such an operation, and a subject in an geographical areathat can be a target of a terrorist attack, for example, a metropolitanarea, a city, an area where there is a large population (for example,above 100,000, above 200,000, above 500,000, above 1 million, above 2million, above 5 million, or above 10 million), or a location or area towhich damage is likely to cause a threat to national security or publichealth (for example, a nuclear power plant, a chemical plant, anairport, or a hospital).

In some embodiments, provided is a method of treating a bacterialinfection in a subject, where the subject is exposed or suspected ofbeing exposed to a bacterium or a component thereof, that includesadministering to the subject an effective amount of a compound disclosedherein, or a tautomer thereof, or a pharmaceutically acceptable salt ofthe compound or tautomer. In another embodiment, provided is a method amethod of preventing a bacterial infection in a subject, where thesubject is at a risk of being exposed to a bacterium or a componentthereof, that includes administering to the subject an effective amountof a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer. In oneembodiment, the bacterium or a component thereof is formulated as anaerosol or power. In another embodiment, the bacterial component is abacterial spore. In some embodiments, the present disclosure relates toa method, use, or compound disclosed herein, wherein the amount ofcompound or a tautomer thereof, or a pharmaceutically acceptable salt ofthe compound or tautomer comprises from 0.1 mg to 1500 mg. For example,a dose of active compound can range from about 0.1 mg to about 1250 mg;about 0.1 mg to about 1000 mg; about 0.1 mg to about 800 mg; about 0.1mg to about 500 mg; about 0.1 mg to about 250 mg; about 0.1 mg to about100 mg; about 0.1 mg to about 50 mg; about 0.1 mg to about 25 mg; about0.1 mg to about 20 mg; about 0.1 mg to about 10 mg; about 0.1 mg toabout 5 mg; about 0.1 mg to about 1 mg; about 0.1 mg to about 0.5 mg;about 0.5 mg to about 1500 mg; about 1 mg to about 1500 mg; about 2.5 mgto about 1500 mg; about 5 mg to about 1500 mg; about 10 mg to about 1500mg; about 50 mg to about 1500 mg; about 100 mg to about 1500 mg; about250 mg to about 1500 mg; about 500 mg to about 1500 mg; about 750 mg toabout 1500 mg; about 1000 mg to about 1500 mg; about 1250 mg to about1500 mg; about 0.25 mg to about 2.5 mg; about 0.5 mg to about 5 mg;about 1 mg to about 10 mg; about 5 to about 20 mg; about 10 mg to about50 mg; about 25 mg to about 75 mg; about 20 mg to about 100 mg; about 50mg to about 200 mg; about 100 mg to about 500 mg; about 250 mg to about750 mg; about 200 mg to about 800 mg; about 500 mg to about 1000 mg; orabout 750 mg to about 1250 mg.

In some embodiments, the present disclosure relates to a method, use, orcompound disclosed herein wherein the compound, or a tautomer thereof,or a pharmaceutically acceptable salt of the compound or tautomer, isadministered optically, ophthalmically, nasally, orally, parenterally,topically, or intravenously.

In some embodiments, the present disclosure relates to a method ofsynthesizing a compound disclosed herein, or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer.

In some embodiments, the present disclosure relates to a medical devicecontaining a compound disclosed herein or a tautomer thereof, or apharmaceutically acceptable salt of the compound or tautomer. In someembodiments, the device is a stent.

3. SYNTHESIS OF THE COMPOUNDS OF THE DISCLOSURE

The compounds of the present disclosure can be synthesized by using artrecognized techniques, such as those described in US 2012-0220566, WO2012/173689, or PCT/US2014/054869, the contents of each of which areincorporated herein by reference in their entireties. The compounds thusobtained can be further purified, for example, by flash columnchromatography, high performance liquid chromatography, crystallization,or any known purification method.

In one embodiment, compounds of the present disclosure can besynthesized according to the exemplary method described below.

The specific approaches and compounds shown in the schemes above are notintended to be limiting. The chemical structures in the schemes hereindepict variables that are hereby defined commensurately with chemicalgroup definitions (moieties, atoms, etc.) of the corresponding positionin the compound formulae herein, whether identified by the same variablename (i.e., R₁, R₂, R₃, etc.) or not. The suitability of a chemicalgroup in a compound structure for use in the synthesis of anothercompound is within the knowledge of one of ordinary skill in the art.

Additional methods of synthesizing compounds of the formulae herein andtheir synthetic precursors, including those within routes not explicitlyshown in schemes herein, are within the means of chemists of ordinaryskill in the art. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe applicable compounds are known in the art and include, for example,those described in Larock R, Comprehensive Organic Transformations, VCHPublishers (1989); Fieser L et al., Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and Paquette L, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995) and subsequent editions thereof.

4. CHARACTERIZATION OF COMPOUNDS OF THE DISCLOSURE

Compounds designed, selected and/or optimized by methods describedabove, once produced, can be characterized using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules can becharacterized by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysisusing such assays. As a result, it can be possible to rapidly screen themolecules disclosed herein for activity, for example, as anti-cancer,anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also,it can be possible to assay how the compounds interact with a ribosomeor ribosomal subunit and/or are effective as modulators (for example,inhibitors) of protein synthesis using techniques known in the art.General methodologies for performing high-throughput screening aredescribed, for example, in Devlin (1998) High Throughput Screening,Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto, those described below.

(1) Surface Binding Studies. A variety of binding assays can be usefulin screening new molecules for their binding activity. One approachincludes surface plasmon resonance (SPR) that can be used to evaluatethe binding properties of molecules of interest with respect to aribosome, ribosomal subunit or a fragment thereof.

SPR methodologies measure the interaction between two or moremacromolecules in real-time through the generation of aquantum-mechanical surface plasmon. One device, (BIAcore Biosensor RTMfrom Pharmacia Biosensor, Piscataway, N.J.) provides a focused beam ofpolychromatic light to the interface between a gold film (provided as adisposable biosensor “chip”) and a buffer compartment that can beregulated by the user. A 100 nm thick “hydrogel” composed ofcarboxylated dextran that provides a matrix for the covalentimmobilization of analytes of interest is attached to the gold film.When the focused light interacts with the free electron cloud of thegold film, plasmon resonance is enhanced. The resulting reflected lightis spectrally depleted in wavelengths that optimally evolved theresonance. By separating the reflected polychromatic light into itscomponent wavelengths (by means of a prism), and determining thefrequencies that are depleted, the BIAcore establishes an opticalinterface which accurately reports the behavior of the generated surfaceplasmon resonance. When designed as above, the plasmon resonance (andthus the depletion spectrum) is sensitive to mass in the evanescentfield (which corresponds roughly to the thickness of the hydrogel). Ifone component of an interacting pair is immobilized to the hydrogel, andthe interacting partner is provided through the buffer compartment, theinteraction between the two components can be measured in real timebased on the accumulation of mass in the evanescent field and itscorresponding effects of the plasmon resonance as measured by thedepletion spectrum. This system permits rapid and sensitive real-timemeasurement of the molecular interactions without the need to labeleither component.

(2) Fluorescence Polarization. Fluorescence polarization (FP) is ameasurement technique that can readily be applied to protein-protein,protein-ligand, or RNA-ligand interactions in order to derive IC₅₀s andKds of the association reaction between two molecules. In this techniqueone of the molecules of interest is conjugated with a fluorophore. Thisis generally the smaller molecule in the system (in this case, thecompound of interest). The sample mixture, containing both theligand-probe conjugate and the ribosome, ribosomal subunit or fragmentthereof, is excited with vertically polarized light. Light is absorbedby the probe fluorophores, and re-emitted a short time later. The degreeof polarization of the emitted light is measured. Polarization of theemitted light is dependent on several factors, but most importantly onviscosity of the solution and on the apparent molecular weight of thefluorophore. With proper controls, changes in the degree of polarizationof the emitted light depends only on changes in the apparent molecularweight of the fluorophore, which in-turn depends on whether theprobe-ligand conjugate is free in solution, or is bound to a receptor.Binding assays based on FP have a number of important advantages,including the measurement of IC₅₀s and Kds under true homogenousequilibrium conditions, speed of analysis and amenity to automation, andability to screen in cloudy suspensions and colored solutions.

(3) Protein Synthesis. It is contemplated that, in addition tocharacterization by the foregoing biochemical assays, the compound ofinterest can also be characterized as a modulator (for example, aninhibitor of protein synthesis) of the functional activity of theribosome or ribosomal subunit.

Furthermore, more specific protein synthesis inhibition assays can beperformed by administering the compound to a whole organism, tissue,organ, organelle, cell, a cellular or subcellular extract, or a purifiedribosome preparation and observing its pharmacological and inhibitoryproperties by determining, for example, its inhibition constant (IC₅₀)for inhibiting protein synthesis. Incorporation of ³H leucine or ³⁵Smethionine, or similar experiments can be performed to investigateprotein synthesis activity. A change in the amount or the rate ofprotein synthesis in the cell in the presence of a molecule of interestindicates that the molecule is a modulator of protein synthesis. Adecrease in the rate or the amount of protein synthesis indicates thatthe molecule is an inhibitor of protein synthesis.

(4) Antimicrobial assays and other evaluation. Furthermore, thecompounds can be assayed for anti-proliferative or anti-infectiveproperties on a cellular level. For example, where the target organismis a microorganism, the activity of compounds of interest can be assayedby growing the microorganisms of interest in media either containing orlacking the compound. Growth inhibition can be indicative that themolecule can be acting as a protein synthesis inhibitor. Morespecifically, the activity of the compounds of interest againstbacterial pathogens can be demonstrated by the ability of the compoundto inhibit growth of defined strains of human pathogens. For thispurpose, a panel of bacterial strains can be assembled to include avariety of target pathogenic species, some containing resistancemechanisms that have been characterized. Use of such a panel oforganisms permits the determination of structure-activity relationshipsnot only in regards to potency and spectrum, but also with a view toobviating resistance mechanisms.

(5) The translation-only assay for ribosomal protein production usespurified 70S ribosomes, corresponding S100 extracts containing thebiological molecules necessary to support protein translation, and mRNAencoding firefly luciferase or another protein reporter. The resultingluminescence signal is proportional to protein translation and isdetermined by a luminescence assay plate reader (i.e. Victor2VMultilabel Reader). This assay is performed with varying concentrationsof potential translation inhibitors in the assay. The resulting data areused to calculate IC50 values of inhibition for the compounds usingappropriate software (i.e. MDL Assay Explorer with a one-sitecompetition model of binding).

The in vitro activity of the compounds of the present disclosure can bedetermined. Antimicrobial testing is typically performed to determinethe minimum inhibitory concentration (MIC). Minimum inhibitoryconcentrations (MICs) are determined by the microdilution method in afinal volume of 100 μl according to protocols outlined by The Clinicaland Laboratory Standards Institute (CLSI). Performance standards forreference strains are assessed within the same experimental design tomaintain quality control. See, for example, Clinical LaboratoryStandards Institute: Methods for dilution antimicrobial susceptibilitytests for bacteria that grow aerobically M7-A8. Approved Standard-EighthEdition. Wayne, Pa.: CLSI; December 2008; and Clinical LaboratoryStandards Institute: Performance Standards for AntimicrobialSusceptibility Testing M100-S20; Approved Standard-Twentieth Edition.Wayne, Pa.: CLSI; June 2010.

For example, an agar-dilution MIC assay could be run using the followingprotocol. Pure cultures of isolates to be tested are grown on ChocolateAgar at 35° C. to 36.5° C. in a CO₂ enriched (5%) atmosphere for 16-18hours. Using a cotton applicator or a bacteriologic loop, isolatedcolonies (or cells from less dense areas of growth on the plate) aresuspended in 5 mL saline. The density of the suspension is then adjustedto contain 108 colony forming units (CFU)/ml by comparison with a 0.5McFarland BaSO₄ turbidity standard. This suspension is then diluted in1:10 in MH broth to give 10⁷ CFU/ml. Using a multichannel pipettor,0.002 mL spots of the bacterial suspension is dispensed onto the surfaceof the medium, i.e., 10⁴ CFU. Each plate of the set of antibioticcontaining media plus a plate of Chocolate Agar or GCS medium (as acontrol to determine that all isolates grew) is inoculated. Theinoculated plates are air-dried at room temperature for approximately 15minutes. The plates are then inverted and incubated at 35° C. to 36.5°C. in a CO₂-enriched (5%) atmosphere for 24 hours. The plates are thenexamined for growth.

Another in vitro assay that can be performed is a time-kill kineticassay. Using this assay, bactericidal activity can be determined bytime-kill methodology as described by Clinical Laboratory StandardsInstitute. For example, the compounds to be tested are added to testflasks at concentrations of 2×-32× the MIC (determined, for example,using the assays described herein). Once dissolved, compounds arediluted in Giolitti Cantoni (GC) broth to a volume of 1 mL at the 25×desired final concentration; a flask containing 1 mL of GC broth withoutcompound is prepared as a growth control. A 0.5 McFarland equivalent isprepared for the test organism, diluted 1:200 in pre-warmed GC broth,and incubated in 5% CO₂-enriched atmosphere at 35° C. for 30 minutesprior to exposure to the test compound. After the 30-minutepre-incubation, 24 mL is removed and added to each test flask for afinal volume of 25 mL. A sample is removed from the growth controlflask, diluted in Phosphate Buffered Saline (PBS) and plated onChocolate Agar (CA) to confirm an inoculum of approximately 5×10⁵CFU/mL. Samples are then removed from all flasks at 1, 2, 4, 6, 8, and24 hours, diluted in PBS and plated on CA to determine the number ofviable cells in each flask. Plate counts are incubated at 35° C. in 5%CO₂-enriched atmosphere for 48 hours and colonies are counted. Platecounts are then graphed.

The antimicrobial and other drug properties of the compounds can furtherbe evaluated in various in vivo mammalian assays, such as a mouse or ratperitonitis infectious models, skin and soft tissue models (oftenreferred to as the thigh model), or a mouse pneumonia model. There aresepticemia or organ infection models known to those skilled in the art.These efficacy models can be used as part of the evaluation process andcan be used as a guide of potential efficacy in humans. Endpoints canvary from reduction in bacterial burden to lethality. For the latterendpoint, results are often expressed as a PD₅₀ value, or the dose ofdrug that protects 50% of the animals from mortality.

To further assess a compound's drug-like properties, measurements ofinhibition of cytochrome P450 enzymes and phase II metabolizing enzymeactivity can also be measured either using recombinant human enzymesystems or more complex systems like human liver microsomes. Further,compounds can be assessed as substrates of these metabolic enzymeactivities as well. These activities are useful in determining thepotential of a compound to cause drug-drug interactions or generatemetabolites that retain or have no useful antimicrobial activity.

To get an estimate of the potential of the compound to be orallybioavailable, one can also perform solubility and Caco-2 assays. Thelatter is a cell line from human epithelium that allows measurement ofdrug uptake and passage through a Caco-2 cell monolayer often growingwithin wells of a 24-well microtiter plate equipped with a 1 micronmembrane. Free drug concentrations can be measured on the basolateralside of the monolayer, assessing the amount of drug that can passthrough the intestinal monolayer. Appropriate controls to ensuremonolayer integrity and tightness of gap junctions are needed. Usingthis same system one can get an estimate of P-glycoprotein mediatedefflux. P-glycoprotein is a pump that localizes to the apical membraneof cells, forming polarized monolayers. This pump can abrogate theactive or passive uptake across the Caco-2 cell membrane, resulting inless drug passing through the intestinal epithelial layer. These resultsare often done in conjunction with solubility measurements and both ofthese factors are known to contribute to oral bioavailability inmammals. Measurements of oral bioavailability in animals and ultimatelyin man using traditional pharmacokinetic experiments will determine theabsolute oral bioavailability.

Experimental results can also be used to build models that help predictphysical-chemical parameters that contribute to drug-like properties.When such a model is verified, experimental methodology can be reduced,with increased reliance on the model predictability.

(5) Animal Pharmacology and Toxicology. The compounds of the presentdisclosure can be evaluated for efficacy in well-known animal models.The following table provides representative animal models for variousinfection indications.

Target Infection Indication Animal Model of Efficacy HAP/VAP Efficacy inmouse and/or rat pneumoniae model vs. respiratory tract infectionpathogens of interest (Streptococcus pneumoniae, including multi-drugresistant Streptococcus pneumoniae, H. influenzae, methicillin resistantStaphylococcus aureus (MRSA), and Pseudomonas. aeruginosa) cSSSIEfficacy in mouse model against pathogens of interest (MRSA, K.pneumoniae) Sepsis Efficacy in mouse peritonitis model vs. pathogens ofinterest (E. coli, K. pneumoniae, E. faecalis, MRSA) cUTI Efficacy inmouse model against E. coli, K. pneumoniae and/or MRSA) Febrileneutropenia Efficacy in mouse peritonitis model against S. aureus, S.epidermidis, S. pneumoniae, S. pyogenes, P. aeruginosaAnimal Model for Complicated Skin and Skin Structure Infections (cSSSI):Murine Skin and Soft Tissue Infection Model of Klebsiella pneumoniae1705966 in Thighs of Neutropenic Female CD-1 Mice

This model is useful to assess the efficacy of compounds of the presentdisclosure in a Klebsiella pneumoniae 1705966 neutropenic mouse thighinfection model using female ICR (CD-1) mice.

Study Design:

Species: Female ICR (CD-1) Mice, 8 to 9 weeks old, weighting 25-29 g.

Inoculum: Klebsiella pneumoniae 17059663 was streaked from frozen stockonto Blood agar (Tryptic Soy Agar+5% Sheep Blood), BD, #221261) andincubated overnight at 35° C. After overnight incubation, enoughbacteria (approx. 1 full loop) to measure OD₆₂₅=0.990 was transferredfrom plate and diluted into 10 ml pre-warmed Mueller-Hinton broth. Thisculture was further diluted 1:1000 into pre-warmed MH broth and grownfor approximately 2 hours at 35° C. with shaking. Each mouse was given0.1 mL of 1:1000 dilution culture injected into both caudal thighmuscles under isoflurane inhalation anesthesia.

Dilution Initial O.D. Final O.D. (after~2 hr. incubation) 1:10 0.1350.424 1:100 0.014 0.215 1:1000 0.001 0.035Neutropenia is induced by intraperitoneal (I.P.) administration ofCyclophosphamide monohydrate on Day −4 (150 mg/kg) and Day −1 (100mg/kg).

Vehicle: 0.9% sodium chloride

Dosing: Each mouse in the treated groups was given the appropriate doseof the compound to be tested in a volume of 0.2 ml, 2 and 8 hrs. postbacterial inoculation.

Time points:

Controls: 0, 2, 6, and 24 hrs.

Treated: 24 hrs.

Sampling: 2 or 3 mice/time point were euthanized via CO₂, and theircaudal thigh muscles excised and homogenized. The thigh muscles wereplaced in 5 ml sterile PBS in Stomacher Filter bag and homogenized withMicroBiomaster80 (Brinkmann) for 60 seconds, normal setting and 1:10dilutions were made per standard protocol in a 96-well plate. Aliquotsof 25 ul for each dilution, as well as the homogenate, were plated onblood agar plates and incubated at 35° C. to determine the CFU/mL overthe time course. After overnight incubation, colonies were counted.

Animal Model for Sepsis:

Murine Peritonitis Model (E. coli, K. Pneumoniae, E. Faecalis, MRSA)

This model is used to evaluate the effect of subcutaneous (SC) treatmentwith compounds of the present disclosure on growth of Escherichia coliATCC 25922 in a mouse peritonitis model using female Swiss Webster mice.

Controls:

Negative: Inoculum only

Inoculum Vehicle Intraperitoneal

Positive: Ciprofloxacin

Study Design:

Species: Female Swiss Webster Mice

Inoculation: Escherichia coli ATCC 25922 is made by adding 1 ml (Apr. 6,2007) stock to 9 ml 0.25% Brewer's Yeast to make (1:10), then 1 ml ofthe (1:10) will be added to 9 ml 0.25% Brewer's Yeast to make (1:100),then 1 ml of the (1:100) will be added to 9 ml 0.25% Brewer's Yeast tomake (1:1000), then 2.5 ml of the (1:1000) will be added to 122.5 ml0.25% Brewer's Yeast to make (1:50,000), 1 ml/mouse will be inoculatedintraperitoneally (IP).

Route of Administration: SC

Dosing: Vehicle for compounds of the present disclosure: Saline or 50 mMSodium phosphate buffer in 10% Captisol in water, pH=7.2.

Dose Administration: Q3H×3 beginning at 30 min post bacterialinoculation

Study Duration: 24 hrs. 0.25% Brewer's Yeast Extract (BYE): Dilute 2%prepared on 11/12/09 (Lot.2158K, MP Biomedicals) 25 ml 2%+175 ml 1× PBS.

Outcome Measures: Colony Forming Unit's from peritoneal wash and spleenhomogenate and drug levels from wash, spleen homogenate, and plasma.

Blood is collected via cardiac puncture while mouse is under CO₂narcosis. The whole blood sample is placed in heparinized eppendorftubes and kept on wet ice until centrifuged (4 min @ 14,000 rpm). Plasmais transferred to 96 deep-well block on dry ice and stored at −20° C.Immediately following blood collection, 2 ml of sterile PBS (phosphatebuffered saline) was injected into the peritoneal cavity with a 25Gneedle. The abdomen was gently massaged, and a small incision was madeto allow access to the peritoneal cavity. The peritoneal wash fluid wascollected using sterile technique, serially diluted 1:10, plated onblood agar plates, and incubated overnight at 35° C.

Spleens were harvested and placed in 1 ml sterile PBS in Stomacher bagand homogenized with MicroBiomaster80 (Brinkmann) for 60 seconds, normalsetting and 1:10 dilutions were made. 25 μl of each dilution, as well asthe homogenate, was plated on blood agar plates and incubated at 35° C.to determine the CFU/mL over the time course. After overnightincubation, colonies were counted.

Other Animal Models

Similarly, other animal infection models can be used for hospitalacquired pneumonia (HAP)/ventilator acquired pneumonia (VAP),complicated urinary tract infections (cUTI), and febrile neutropenia.

5. FORMULATION AND ADMINISTRATION

The compositions and methods of the present disclosure can be practicedby delivering the compounds of the present disclosure using a means fordelivery e.g., any suitable carrier. The dose of active compound, modeof administration and use of suitable carrier will depend upon theintended patient or subject and the targeted microorganism, e.g., thetarget bacterial organism. The formulations, both for human medical useand veterinary use, of compounds according to the present disclosuretypically include such compounds in association with a pharmaceuticallyacceptable carrier.

The carrier(s) should be “acceptable” in the sense of being compatiblewith compounds of the present disclosure and not deleterious to therecipient. Pharmaceutically acceptable carriers, in this regard, areintended to include any and all solvents, dispersion media, coatings,absorption delaying agents, and the like, compatible with pharmaceuticaladministration. Supplementary active compounds (identified or designedaccording to the disclosure and/or known in the art) also can beincorporated into the compositions. In some embodiments, formulationsare prepared by bringing the compound into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

A pharmaceutical composition of the disclosure should be formulated tobe compatible with its intended route of administration. Solutions orsuspensions can include the following components: a sterile diluent suchas water, saline solution, fixed oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents; antibacterial agents suchas benzyl alcohol or methyl parabens; antioxidants such as ascorbic acidor sodium bisulfite; chelating agents such as ethylenediaminetetraaceticacid; buffers such as acetates, citrates or phosphates and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

Formulations for parenteral administration can also include glycocholatefor buccal administration, methoxysalicylate for rectal administration,or citric acid for vaginal administration. The parenteral preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic. Suppositories for rectal administration alsocan be prepared by mixing the drug with a non-irritating excipient suchas cocoa butter, other glycerides, or other compositions which are solidat room temperature and liquid at body temperatures. Formulations alsocan include, for example, polyalkylene glycols such as polyethyleneglycol, oils of vegetable origin, and hydrogenated naphthalenes.Formulations for direct administration can include glycerol and othercompositions of high viscosity. Other potentially useful parenteralcarriers for these drugs include ethylene-vinyl acetate copolymerparticles, osmotic pumps, implantable infusion systems, and liposomes.Formulations for inhalation administration can contain as excipients,for example, lactose, or can be aqueous solutions containing, forexample, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate,or oily solutions for administration in the form of nasal drops, or as agel to be applied intranasally. Retention enemas also can be used forrectal delivery.

Formulations of the present disclosure suitable for oral administrationcan be in the form of: discrete units such as capsules, gelatincapsules, sachets, tablets, troches, or lozenges, each containing apredetermined amount of the drug; a powder or granular composition; asolution or a suspension in an aqueous liquid or non-aqueous liquid; oran oil-in-water emulsion or a water-in-oil emulsion. The drug can alsobe administered in the form of a bolus, electuary or paste. A tablet canbe made by compressing or molding the drug optionally with one or moreaccessory ingredients. Compressed tablets can be prepared bycompressing, in a suitable machine, the drug in a free-flowing form suchas a powder or granules, optionally mixed by a binder, lubricant, inertdiluent, surface active or dispersing agent. Molded tablets can be madeby molding, in a suitable machine, a mixture of the powdered drug andsuitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients. Oral compositions preparedusing a fluid carrier for use as a mouthwash include the compound in thefluid carrier and are applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). Itshould be stable under the conditions of manufacture and storage andshould be preserved against the contaminating action of microorganismssuch as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (for example,glycerol, propylene glycol, and liquid polyethylene glycol), andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. In many cases, it will be preferable to include isotonicagents, for example, sugars, polyalcohols such as mannitol, sorbitol,and sodium chloride in the composition. Prolonged absorption of theinjectable compositions can be brought about by including in thecomposition an agent which delays absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfilter sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation include vacuumdrying and freeze-drying which yields a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Formulations suitable for intra-articular administration can be in theform of a sterile aqueous preparation of the drug that can be inmicrocrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems can also be used to present the drug for bothintra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eyetreatment, include liquid or semi-liquid preparations such as liniments,lotions, gels, applicants, oil-in-water or water-in-oil emulsions suchas creams, ointments or pastes; or solutions or suspensions such asdrops. Formulations for topical administration to the skin surface canbe prepared by dispersing the drug with a dermatologically acceptablecarrier such as a lotion, cream, ointment or soap. Useful are carrierscapable of forming a film or layer over the skin to localize applicationand inhibit removal. For topical administration to internal tissuesurfaces, the agent can be dispersed in a liquid tissue adhesive orother substance known to enhance adsorption to a tissue surface. Forexample, hydroxypropylcellulose or fibrinogen/thrombin solutions can beused to advantage. Alternatively, tissue-coating solutions, such aspectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling orspray formulations) dispensed with a spray can, a nebulizer, or anatomizer can be used. Such formulations can be in the form of a finepowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations. In the case ofself-propelling solution and spray formulations, the effect can beachieved either by choice of a valve having the desired spraycharacteristics (i.e., being capable of producing a spray having thedesired particle size) or by incorporating the active ingredient as asuspended powder in controlled particle size. For administration byinhalation, the compounds also can be delivered in the form of anaerosol spray from pressured container or dispenser which contains asuitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants can include, for example, for transmucosaladministration, detergents and bile salts. Transmucosal administrationcan be accomplished through the use of nasal sprays or suppositories.For transdermal administration, the active compounds typically areformulated into ointments, salves, gels, or creams.

The active compounds can be prepared with carriers that will protect thecompound against rapid elimination from the body, such as a controlledrelease formulation, including implants and microencapsulated deliverysystems. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Liposomal suspensions can also beused as pharmaceutically acceptable carriers.

Oral or parenteral compositions can be formulated in dosage unit formfor ease of administration and uniformity of dosage. Dosage unit formrefers to physically discrete units suited as unitary dosages for thesubject to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the disclosure are dictated by and directlydependent on the unique characteristics of the active compound and thetherapeutic effect to be achieved, and the limitations inherent in theart of compounding such an active compound for the treatment ofindividuals. Furthermore, administration can be by periodic injectionsof a bolus, or can be made more continuous by intravenous, intramuscularor intraperitoneal administration from an external reservoir (e.g., anintravenous bag).

Where adhesion to a tissue surface is desired the composition caninclude the drug dispersed in a fibrinogen-thrombin composition or otherbioadhesive. The compound then can be painted, sprayed or otherwiseapplied to the desired tissue surface. Alternatively, the drugs can beformulated for parenteral or oral administration to humans or othermammals, for example, in effective amounts, e.g., amounts that provideappropriate concentrations of the drug to target tissue for a timesufficient to induce the desired effect.

Where the active compound is to be used as part of a transplantprocedure, it can be provided to the living tissue or organ to betransplanted prior to removal of tissue or organ from the donor. Thecompound can be provided to the donor host. Alternatively, or, inaddition, once removed from the donor, the organ or living tissue can beplaced in a preservation solution containing the active compound. In allcases, the active compound can be administered directly to the desiredtissue, as by injection to the tissue, or it can be providedsystemically, either by oral or parenteral administration, using any ofthe methods and formulations disclosed herein. Where the drug comprisespart of a tissue or organ preservation solution, any commerciallyavailable preservation solution can be used to advantage. For example,useful solutions known in the art include Collins solution, Wisconsinsolution, Belzer solution, Eurocollins solution and lactated Ringer'ssolution.

Generally, an effective amount of dosage of active compound will be inthe range of from about 0.1 mg/kg to about 100 mg/kg of body weight/day,for example, from about 1.0 mg/kg to about 50 mg/kg of body weight/day.In some embodiments, the dosage of active compound is in the range offrom about 0.1 mg/kg to about 1.0 mg/kg of body weight/day; from about0.1 mg/kg to about 5 mg/kg of body weight/day; from about 0.1 mg/kg toabout 10 mg/kg of body weight/day; from about 0.1 mg/kg to about 25mg/kg of body weight/day; from about 0.1 mg/kg to about 50 mg/kg of bodyweight/day; from about 1.0 mg/kg to about 5.0 mg/kg of body weight/day;from about 1.0 mg/kg to about 10 mg/kg of body weight/day; from about1.0 mg/kg to about 20 mg/kg of body weight/day; from about 1.0 mg/kg toabout 25 mg/kg of body weight/day; from about 1.0 mg/kg to about 40mg/kg of body weight/day; from about 1.0 mg/kg to about 100 mg/kg ofbody weight/day; from about 10 mg/kg to about 100 mg/kg of bodyweight/day; from about 25 mg/kg to about 100 mg/kg of body weight/day;from about 50 mg/kg to about 100 mg/kg of body weight/day; from about5.0 mg/kg to about 50 mg/kg of body weight/day; from about 10 mg/kg toabout 50 mg/kg of body weight/day; or from about 25 mg/kg to about 50mg/kg of body weight/day.

The amount administered will also likely depend on such variables as thetype of surgery or invasive medical procedure, the overall health statusof the patient, the relative biological efficacy of the compounddelivered, the formulation of the drug, the presence and types ofexcipients in the formulation, and the route of administration. Also, itis to be understood that the initial dosage administered can beincreased beyond the above upper level in order to rapidly achieve thedesired blood-level or tissue level, or the initial dosage can besmaller than the optimum.

Nonlimiting doses of active compound comprise from about 0.1 mg to about1500 mg per dose. For example, a dose of active compound can range fromabout 0.1 mg to about 1250 mg; about 0.1 mg to about 1000 mg; about 0.1mg to about 800 mg; about 0.1 mg to about 500 mg; about 0.1 mg to about250 mg; about 0.1 mg to about 100 mg; about 0.1 mg to about 50 mg; about0.1 mg to about 25 mg; about 0.1 mg to about 20 mg; about 0.1 mg toabout 10 mg; about 0.1 mg to about 5 mg; about 0.1 mg to about 1 mg;about 0.1 mg to about 0.5 mg; about 0.5 mg to about 1500 mg; about 1 mgto about 1500 mg; about 2.5 mg to about 1500 mg; about 5 mg to about1500 mg; about 10 mg to about 1500 mg; about 50 mg to about 1500 mg;about 100 mg to about 1500 mg; about 250 mg to about 1500 mg; about 500mg to about 1500 mg; about 750 mg to about 1500 mg; about 1000 mg toabout 1500 mg; about 1250 mg to about 1500 mg; about 0.25 mg to about2.5 mg; about 0.5 mg to about 5 mg; about 1 mg to about 10 mg; about 5to about 20 mg; about 10 mg to about 50 mg; about 25 mg to about 75 mg;about 20 mg to about 100 mg; about 50 mg to about 200 mg; about 100 mgto about 500 mg; about 250 mg to about 750 mg; about 200 mg to about 800mg; about 500 mg to about 1000 mg; or about 750 mg to about 1250 mg.

As is understood by one of ordinary skill in the art, generally, whendosages are described for a pharmaceutical active, the dosage is givenon the basis of the parent or active moiety. Therefore, if a salt,hydrate, or another form of the parent or active moiety is used, acorresponding adjustment in the weight of the compound is made, althoughthe dose is still referred to on the basis of the parent or activemoiety delivered. As a nonlimiting example, if the parent or activemoiety of interest is a monocarboxylic acid having a molecular weight of250, and if the monosodium salt of the acid is desired to be deliveredto be delivered at the same dosage, then an adjustment is maderecognizing that the monosodium salt would have a molecular weight ofapproximately 272 (i.e., minus 1H or 1.008 atomic mass units and plus 1Na or 22.99 atomic mass units). Therefore, a 250 mg dosage of the parentor active compound would correspond to about 272 mg of the monosodiumsalt, which would also deliver 250 mg of the parent or active compound.The another way, about 272 mg of the monosodium salt would be equivalentto a 250 mg dosage of the parent or active compound.

In some embodiments, pyrrolocytosines, such as the compounds ortautomers thereof, or pharmaceutically acceptable salts of the compoundsor tautomers, as provided herein, can exhibit an acute clinicalsyndrome, which manifests as a C_(max)-driven hemodynamic effect and isassociated with immediate clinical signs such as labored breathing.C_(max) is the peak concentration a molecule reaches in the plasma(e.g., directly following intravenous administration), and is expressedgenerally in micrograms/milliliter. The syndrome is dose-dependent,meaning that the higher the amount of drug given, the more severe arethe effects. In some embodiments, this is the limiting toxicity for theclass. In some embodiments, however, the efficacy for thepyrrolocytosines, including the compounds or tautomers thereof, orpharmaceutically acceptable salts of the compounds or tautomers, asprovided herein, is not driven by the C_(max) but rather by the AUC(Area-Under-the-plasma-drug-concentration-time-Curve), which is anexpression of the total body exposure to the drug and is expressedgenerally in micrograms*hour/milliliter. In rat studies with severalpyrrolocytosines, including selected compounds or tautomers thereof, orpharmaceutically acceptable salts of the compounds or tautomers asprovided herein, it has been shown that increasing the length, orduration, of the intravenous administration results in one or more ofeffectively modulating or eliminating the clinical syndrome anddepressing the concentration maximum. In some embodiments, these effectsresult in a short distribution half-life but still afford drug exposuresnecessary for efficacy.

FORMULATION EXAMPLES IA. Formulation for Intravenous Administration

Ingredients Amount Antimicrobial Compound 0.1-1500 total mg of thepresent disclosure Dextrose, USP 50 mg/ml Sodium citrate, USP 1.60-1.75mg/ml Citric Acid, USP 0.80-0.90 mg/ml Water, USP q.s

This formulation for intravenous administration is formulated by heatingwater for injection to about 60° C. Next the sodium citrate, citric acidand dextrose are added and stirred until dissolved. A solution oraqueous slurry of the antimicrobial compound is added to the previousmixture and stirred until dissolved. The mixture is cooled to 25° C.with stirring. The pH is measured and adjusted if necessary. Lastly themixture is brought to the desired volume, if necessary, with water forinjection. The mixture is filtered, filled into the desired container(vial, syringe, infusion container, etc.), over wrapped and terminallymoist heat sterilized.

This formulation is useful for intravenous administration, either bolusor infusion, to a patient for treating, preventing, reducing the riskof, or delaying the onset of infection.

IB. Formulation for Intravenous Administration

This formulation for intravenous administration utilizes 6.5 nM tartaricacid buffer in 5% Dextrose, and has a pH of 4.4. This formulation isuseful for intravenous administration, either bolus or infusion, to apatient for treating, preventing, reducing the risk of, or delaying theonset of infection.

II. Lyophilisate for Reconstitution

Alternatively, the antimicrobial compound can be provided as alyophilisate which can be reconstituted before intravenous orintramuscular administration.

Ingredient mg per injection vial Antimicrobial Compound 0.1-1500 of thepresent disclosure Cyclodextrin 1500

Reconstitution solution for a volume to be administered of 50 ml(infusion): 5% aqueous glucose solution.

Reconstitution solution for a volume to be administered of 15 ml(bolus): 3.3% aqueous glucose solution.

The foregoing lyophilisate is useful for reconstitution and intravenousadministration, either bolus or infusion, to a patient for treating,preventing, reducing the risk of, or delaying the onset of infection.

III. Lyophilisate for Reconstitution

Ingredient mg per injection vial Antimicrobial Compound 0.1-1500 of thepresent disclosure soya lecithin 2250 Sodium cholate 1500

Reconstitution solution for a volume to be administered of 50 ml(infusion): 4% aqueous glucose solution.

Reconstitution solution for a volume to be administered of 15 ml(bolus): 2% aqueous glucose solution

The foregoing lyophilisate is useful for reconstitution and intravenousadministration, either bolus or infusion, to a patient for treating,preventing, reducing the risk of, or delaying the onset of infection.

IV. Lyophilisate for Reconstitution

Ingredient mg per injection vial Antimicrobial Compound 0.1-1500 of thepresent disclosure soya lecithin 900 Sodium glycocholate 540

Reconstitution solution for a volume to be administered of 15 ml(bolus): 3.3% aqueous glucose solution.

The foregoing lyophilisate is useful for reconstitution and intravenousadministration, either bolus or infusion, to a patient for treating,preventing, reducing the risk of, or delaying the onset of infection.

V. Tablet for Oral Administration

Ingredients Per Tablet Per 4000 Tablets Antimicrobial Compound 0.1-1500mg 0.4-6000 g of the present disclosure Anhydrous Lactose, NF 110.45 mg441.8 g Microcrystalline  80.0 mg 320.0 g Cellulose NF MagnesiumStearate  1.00 mg  4.0 g Impalpable Powder NF Croscarmellose Sodium 2.00 mg  8.0 g NF Type A

The antimicrobial compound (any of the compounds equivalent to thedesired delivery strength, e.g., 50 to 1500 mg per tablet) is premixedwith ⅓ of the microcrystalline cellulose NF and ½ of the anhydrouslactose NF in a ribbon blender for 5 minutes at 20 RPM. To the premix isadded the remaining ⅔ of the microcrystalline cellulose NF and theremaining ½ of the anhydrous lactose NF. This is blended for 10 minutesat 20 RPM. Croscarmellose sodium is added to the blended powders andmixed for 5 minutes at 20 RPM. Finally, the magnesium stearate is addedto the mixture by passing through a 90 mesh screen and blended for anadditional 5 minutes at 20 RPM. The lubricated mixture is compressed toprovide tablets of 500 mg active ingredient.

These tablets are useful for oral administration to a patient fortreating, prevention, reducing the risk of, or delaying the onset ofinfection.

6. EXAMPLES

Nuclear magnetic resonance (NMR) spectra were obtained on a BrukerAvance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300spectrometer. Common reaction solvents were either high performanceliquid chromatography (HPLC) grade or American Chemical Society (ACS)grade, and anhydrous as obtained from the manufacturer unless otherwisenoted. “Chromatography” or “purified by silica gel” refers to flashcolumn chromatography using silica gel (EM Merck, Silica Gel 60, 230-400mesh) unless otherwise noted.

The compounds or tautomers thereof, or pharmaceutically acceptable saltsof the compounds or tautomers of the present disclosure can be preparedusing known chemical transformations adapted to the particular situationat hand.

Some of the abbreviations used in the following experimental details ofthe synthesis of the examples are defined below: h or hr=hour(s);min=minute(s); mol=mole(s); mmol=millimole(s); M=molar; μM=micromolar;g=gram(s); μg=microgram(s); rt=room temperature; L=liter(s);mL=milliliter(s); Et₂O=diethyl ether; THF=tetrahydrofuran; DMSO=dimethylsulfoxide; EtOAc=ethyl acetate; Et₃N=triethylamine; i-Pr₂NEt orDIPEA=diisopropylethylamine; CH₂Cl₂=methylene chloride;CHCl₃=chloroform; CDCl₃=deuterated chloroform; CCl₄=carbontetrachloride; MeOH=methanol; CD₃OD=deuterated methanol; EtOH=ethanol;DMF=dimethylformamide; BOC=t-butoxycarbonyl; CBZ=benzyloxycarbonyl;TBS=t-butyldimethylsilyl; TBSCl=t-butyldimethylsilyl chloride;TFA=trifluoroacetic acid; DBU=diazabicycloundecene;TBDPSCl=t-butyldiphenylchlorosilane; Hunig'sBase=N,N-diisopropylethylamine; DMAP=4-dimethylaminopyridine; CuI=copper(I) iodide; MsCl=methanesulfonyl chloride; NaN₃=sodium azide;Na₂SO₄=sodium sulfate; NaHCO₃=sodium bicarbonate; NaOH=sodium hydroxide;MgSO₄=magnesium sulfate; K₂CO₃=potassium carbonate; KOH=potassiumhydroxide; NH₄OH=ammonium hydroxide; NH₄Cl=ammonium chloride;SiO₂=silica; Pd—C=palladium on carbon;Pd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II); Cs₂CO₃=cesium carbonate; Zn=zinc; LiCl=lithium chloride;DMF=N,N-dimethylformamide; 9-BBN=9-Borabicyclo[3.3.1]nonane;K₃PO₄=potassium phosphate; DMA=N,N-dimethylacetamide; DIBAL andDIBAL-H=diisobutylaluminum hydride; m-CPBA=meta-chloroperoxybenzoicacid; KOAc=potassium acetate; B₂Pin₂=bis(pinacolato)diboron;Cu(OAc)₂=copper (II) acetate; TMEDA=tetramethylethylenediamine;Bz₂O=benzoyl anhydride; DIPEA=N,N-diisopropylethylamine;Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0); TEA=triethylamine;MsCl=mesityl chloride; HBr=hydrogen bromide; AcOH=acetic acid;IPAC=isopropyl acetate; EDTA=ethylenediaminetetraacetic acid.

Exemplary compounds synthesized in accordance with the disclosure arelisted in Tables 1. A bolded or dashed bond is shown to indicate aparticular stereochemistry at a chiral center, whereas a wavy bondindicates that the substituent can be in either orientation or that thecompound is a mixture thereof.

The compounds of the present disclosure can be prepared, formulated, anddelivered as salts. For convenience, the compounds are generally shownwithout indicating a particular salt form.

The compounds of the present disclosure can be made using syntheticchemical techniques well known to those of skill in the art.

Example 1: Syntheses of Compound 34

Preparation of Intermediate 2a

4-Bromobenzaldehyde 1a (100.0 g, 540.5 mmol) was added in severalportions to a solution of (S)-(−)-2-methyl-2-propanesulfinamide (65.51g, 540.5 mmol) in CH₂Cl₂ (495 mL) at room temperature. The mixture wasstirred under argon until all solids were dissolved, and then Cs₂CO₃(176.1 g, 540.5 mmol) was added in several portions. The mixture wasstirred and heated to gentle reflux (42-43° C.). After 16 h it wascooled to 0-5° C., and water (500 mL) was slowly added at 15° C. Themixture was stirred at 15-20° C. for 10 min, the phases were separated,and the organic phase was washed with water (250 mL). Afterwards, theorganic layer was concentrated in vacuo to about 250 g, additionalanhydrous CH₂Cl₂ (300 mL) was added, the solution was concentrated to aconstant mass, then dried at room temperature to give sulfinylimine 2aas a pale yellow oil (156.4 g, 99%).

Preparation of Intermediate 3a

To a solution of sulfinylimine 2a (85.87 g, 297.9 mmol) in DMF (450 mL)at 35° C. was added lithium chloride (25.3 g, 595.8 mmol) over 2 min.Afterwards, the mixture was cooled to 25° C. and H₂O (4.56 g, 0.85 molequivalent) was added. The mixture was stirred at 20-25° C. for 5 min,and then freshly activated zinc powder (38.95 g; 595.8 mmol) was added.Immediately afterwards, allyl bromide (72.1 g; 595.8 mmol) was addeddropwise to the mixture over 10 min at 55° C. The temperature wasmaintained at 45-60° C. for the next 20 minutes. Subsequently, thecooling bath was removed and the mixture was stirred to 30-45° C. over40-60 min. After reaction completion, the mixture was cooled to 10-15°C. and IPAC (560 mL) was added, followed by the dropwise addition of H₂O(400 mL) at 25° C. The resulting mixture was cooled to 15-20° C., and 1NHCl/H₂O (550 mL, 6.4 Vol, 0.92 equiv./zinc) was added dropwise at 25° C.Afterwards, IPAC (200 mL) was added and the mixture was stirred for 20min at at pH of 6. The phases were separated, the organic phase waswashed with 5% EDTA solution (pH=7.5; 400 mL), and then with water(2×500 mL). The organic phase was concentrated in vacuo to a constantmass, affording compound 3a (98.02 g, by ¹H-NMR contains 2.8 wt % IPAC;95.27 g, 97% yield).

Preparation of Intermediate 5a

Compound 3a (85.0 g, 257.4 mmol) was dissolved in THE (210 mL). Thesolution was loaded under argon into a 3 L reactor, stirred and cooledusing a water bath at 15-17° C. A solution of 9-BBN in THF (0.5 M; 927mL, 463.3 mmol) was added dropwise at 17-20° C., over 20 min. Themixture was stirred at 20-22° C. for 50 min. Subsequently, a solution ofK₃PO₄/H₂O (2.0 M, in water; 258 mL) was added dropwise over 10 min at22° C. The resulting mixture was stirred for 5 min, and a solution oft-butyl (Z)-3-iodoacrylate 4a (75.2 g, 296.0 mmol) in THF (50 mL,anhydrous) was added over 5 min. Pd(PPh₃)₄ (7.4 g, 6.43 mmol) was addedand the mixture was stirred at 50-55° C. for 3 h. The mixture was cooledto room temperature, followed by a dropwise addition of water (250 mL)under argon. The phases were separated, the organic phase wasconcentrated and the residue was partitioned between IPAC (600 mL) andH₂O (400 mL). The organic layer was washed with water (2×400 mL) andconcentrated in vacuo to a thick oil (208 g). This material was purifiedon a plug of silica (230-400 mesh, 1.5 kg), eluting with a gradient of30%-55% EtOAc/heptane (20 L), basing collection of fractions on HPLCanalysis. This gave the acrylate 5a (103.0 g, 82.6%) as a light-brown,thick oil.

Preparation of Intermediate 6a

Compound 5a (101.0 g, 220.3 mmol) was dissolved in dimethylacetamide(605 mL). The solution was loaded under argon into a 3 L reactor, andCs₂CO₃ (358.4 g, 1.10 mol) was added. The mixture was stirred at roomtemperature for 10 min, and then heated at 50-52° C. for 8 h, followedby stirring at room temperature for 14 h. Subsequently, the mixture wascooled to 5-10° C. and IPAC (600 mL) was added, followed by an additionof H₂O (600 mL) at 30° C., then saturated aqueous NH₄Cl (600 mL) over 5min, resulting in a solution having a pH of 8.5. The mixture was stirredfor 10 min at room temperature and the phases were separated. Theorganic phase was washed with water (2×500 mL) and concentrated in vacuoto give crude product 6a as a tan solid (111.0 g). This sample wasdissolved at 60° C. in IPAC (200 mL). Heptane (250 mL) was added, themixture was cooled to room temperature, seeded with compound 6a (0.2 g),then stirred at room temperature for 14 h. The product was filtered,washed with heptane, and dried at 40° C. to afford product 6a (40.94 g,white needles).

Preparation of Intermediate 7a

A solution of piperidine 6a (71.7 g, 156.4 mmol) in THE (360 mL) wasplaced under argon in a 3 L reactor. DIBAL-H/THF (1.0M; 469 mL, 469mmol) was added dropwise at 23-28° C. over 40 min. Afterwards, themixture was stirred at 22-27° C. for 3 h, and then it was cooled to 0-5°C. and IPAC (940 mL) was slowly added at 15° C. The mixture was stirredfor 10 min, and then it was added slowly, at 20° C., to a 5 L reactorcontaining a solution of potassium-sodium tartrate tetrahydrate (460 g;1.63 mol) in water (1.0 L) that had been previously to 5-10° C. Afterthe addition, the cooling bath was removed, and the mixture was stirredat room temperature for 3 h. The phases were separated, the organicphase was concentrated in vacuo to 320 g, during which rapidprecipitation occurred. The mixture was left standing at roomtemperature for 14 h, the solid was filtered, washed with IPAC (50 mL),and dried at 50° C., affording the alcohol 7a (53.5 g, 88%).

Preparation of Intermediate 8a

50 g (129 mmol) of 7a was dissolved in 1000 ml of dichloromethane,resulting in a dark brown solution with some undissolved solid. mCPBA(44.6 g, 258 mmol) was added in six portions over 30 minutes (it wasobserved that the dark brown color of the solution of 7a fades afteraddition of mCPBA). The resulting clear solution was heated to 35-40° C.in an oil bath for 3 h. The reaction mixture was cooled to roomtemperature, 2M K₂CO₃ solution (500 ml) was added, and the mixture wasstirred for 15 minutes. The reaction mixture was transferred to aseparatory funnel and the layers partitioned. The organic layer wasconcentrated to afford ˜53 g of an off-white solid which was purifiedusing Combiflash chromatography (330 g column size) to afford 45.95 g(88%) 8a as a white solid.

Preparation of Intermediate 9a

Compound 8a (45.9 g, 113.6 mmol) was dissolved in DMSO (300 ml). To thissolution was added bis(pinacolato)diboron (43.3 g, 170.4 mmol), KOAc(33.4 g, 340.8 mmol), and PdCl₂(dppf)CH₂Cl₂ (4.7 g, 5.7 mmol) underargon. The resulting solution was heated in an oil bath at 80° C. underan argon atmosphere for 15 h. After completion of reaction as determinedby LC-MS, the reaction mixture was cooled to rt, and diluted with coldwater (300 ml) and EtOAc (300 ml). The resulting emulsion was filteredthrough celite to remove suspended particles, the layers werepartitioned, and the aqueous layer was extracted with EtOAc. Thecombined organic layers were concentrated to obtain a black, viscous oilwhich was purified by flash chromatography over silica gel to afford50.64 g (99%) of 9a as a foam.

Preparation of Intermediate 10a

Compound 9a (28.0 g, 62.1 mmol) was dissolved in 1 L of MeOH. 200 mL ofwater was added to the resulting solution slowly, then additional MeOHwas added as needed to eliminate the turbidity that developed after theaddition of water. To this solution 5-iodocytosine (17.7 g, 75.5 mmol)was added at RT to result in a first solution. In a separate flask, 100ml MeOH:water (4:1) was added to Cu(OAc)₂.H₂O (13.7 g, 68.31 mmol), thenTMEDA (37.4 ml, 248.4 mmol) was added to this mixture slowly, resultingin a deep blue second solution that was stirred at RT for 10 minutes.Afterwards, the second solution was added to the first solution. Air wasbubbled slowly in the resulting reaction mixture. After stirring at RTfor 7 hr, the reaction mixture was concentrated in vacuo to remove asmuch as MeOH as possible (˜1 L removed). NH₄OH (300 ml) and CH₂Cl₂ (400ml) was added and resulting solution was stirred at RT overnight (˜12h). The reaction mixture was filtered to remove the precipitated solid,which was washed with 10% MeOH in dichloromethane. The solid was driedto afford 9.2 g (26%) of 10a as a white solid. The filtrate wasextracted with 10 to 20% MeOH in dichloromethane, the washed with waterand brine to afford 24.48 g (70%) of 10a as a green foam. Total yield96%.

Preparation of Intermediates 11a and 12a

45.03 g (80.34 mmol) of crude 10a was dissolved in dry DMF (250 ml). Tothe solution was added benzoic anhydride (20.9 g, 92.5 mmol) in portions(alternatively, it can be added as a solution in anhydrous DMF). Theresulting solution was heated at ˜50-55° C. in an oil bath under argonfor 20 h. The reaction mixture was cooled to RT, water and saturatedsodium bicarbonate solution was added, then the mixture was stirred for15 min. The mixture was extracted with EtOAc, then the organic layer wasconcentrated and purified using Combiflash to afford 30.69 g (58%) of11a and 12.45 g (17%) of 12a as a foam.

Preparation of Intermediate 14a

To a solution of iodobenzamide 11a (20.3 g, 30.57 mmol) in DMF (120 mL)was added DIPEA (16.0 mL, 91.71 mmol) and the reaction mixture wasstirred for 10 min. Pd(PPh₃)₄ (1.76 g, 1.53 mmol) and CuI (0.58 g, 3.06mmol) were added, followed by heating to 50° C. over 10 minutes. Then asolution of the alkyne (13a) in DMF (30 mL) was added and stirring wascontinued for 15 h at 70° C. When the LCMS showed the completion ofreaction, it was cooled to ambient temperature and MeOH (200 mL) wasadded, stirring for 3 h at 70° C. When the LCMS showed the completion ofdebenzoylation and formation of 14a, it was cooled to room temperature,the methanol was evaporated, and 200 ml of water was added. The productwas extracted using ethyl acetate (3×100 ml) and the combined organiclayers were washed with water (100 ml), 14% ammonium hydroxide (2×100ml), water (100 ml), and brine (100 ml). It was then dried over sodiumsulfate, concentrated, and purified by flash column chromatography oversilica gel eluting with CH₂Cl₂ and 90% CH₂Cl_(2+9.8)% methanol+0.2%NH₄OH (i.e., “CMA”) to obtain 18.75 g (yield, 76%) of 14a as an orangesolid.

Preparation of Intermediate 15a

To a solution of the alcohol 14a (18.75 g, 23.3 mmol) in MeOH (250 mL)were added silathiol (5 g) and activated charcoal (5 g). The mixture wasstirred overnight at ambient temperature. The solution was filtered overa bed of celite (10 g) and was washed with additional MeOH (2×100 mL).The combined filtrates were concentrated and purified by flash columnchromatography over silica gel eluting with CH₂Cl₂ and 90% CH₂Cl₂+9.8%methanol+0.2% NH₄OH (i.e., “CMA”) to obtain (17.0 g, 21.1 mmol)metal-free 14a as a golden orange solid. To a solution of the solid inCH₂Cl₂ (200 mL) at −5° C. were added TEA (2.63 mL, 18.99 mmol) and MsCl(1.37 mL, 17.94 mmol), and stirring was continued for 15 minutes. WhenLCMS indicated near complete conversion of the alcohol to mesylate, itwas diluted with ice water (50 mL) and brine (100 mL). The organic layerwas separated and the aqueous layer was extracted with additional CH₂Cl₂(2×150 mL). The combined organic layers were dried over sodium sulfateand concentrated to dryness. To this crude mesylate in EtOH (200 mL) wasadded thiourea (8.03 g, 105.5 mmol), and the mixture was stirred at 65°C. for 13 h. When LCMS indicated near complete conversion of mesylate toisothiourea, it was then concentrated and diluted with water (150 mL)and saturated NaHCO₃ (50 mL). The resulting mixture was extracted with10% MeOH in EtOAc (3×200 mL), and the combined organic layers were driedover sodium sulfate, concentrated in vacuo, and purified by flash columnchromatography over silica gel eluting with CH₂Cl₂ and 90% CH₂Cl₂+9.8%methanol+0.2% NH₄OH (i.e., “CMA”) to obtain 15.0 g (yield, 75.0%) of 15aas an orange solid.

Preparation of Compound 34

To a solution of 15a (15.0 g, 17.35 mmol) in anhydrous methanol (50 mL)under an argon atmosphere was added 120 mL of HBr solution (33% inacetic acid) at 0° C. This was stirred for 10 min after which thecooling bath was removed. The stirring was continued at room temperatureovernight. The solution was concentrated in vacuo, then azeotroped withtoluene and ethanol (50 mL each) for 2 times and purified by combiflashusing C18 stationary phase (Column: Silicycle 300 g Catalog:FLH-R33230B-IS330). Desired fractions were combined and concentrated todryness. TFA salt was fully exchanged with HCl (6N aq., 100 ml×1 with100 ml of ethanol) and lyophilized to obtain 8.5 g (yield, 65%) of 34 asgolden yellow solid. ¹H NMR (300 MHz, D2O): δ 8.43 (s, 1H), 7.68 (d,J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.39 (d, J=6.5 Hz, 1H), 7.31 (d,J=5.4 Hz, 1H), 6.80 (s, 1H), 4.62-4.58 (m, 1H), 3.87-3.85 (m, 1H),3.36-3.17 (m, 3H), 2.64-2.48 (m, 3H), 2.28-1.91 (m, 7H), 1.68-1.52 (m,4H), 1.25 (d, J=6.6, 3H); MS (ESI) m/z [M+H]+; calcd for C₃₁H₃₇ClFN₇OS;610.2, found 610.5.

Example 2: Syntheses of Compound 41

To a solution of 14a (0.5 g, 0.62 mmol) in CH₂Cl₂ (5 mL) at 0° C. wereadded TEA (0.6 mL, 1.86 mmol) and MsCl (0.72 mL, 0.9 mmol). Stirring wascontinued for 3 h, then the reaction was warmed to room temperature andstirred for 1 h. It was then diluted with ice-cold water (10 mL) andbrine (10 mL). The organic layer was separated and the aqueous layer wasextracted with additional CH₂Cl₂ (2×10 mL). The combined organic layerswere dried over sodium sulfate and concentrated to dryness to afford0.40 g of the mesylate. To this crude mesylate in EtOH (5 mL) was addedN-methyl thiourea (0.42 g, 4.5 mol) and stirred at 70° C. for 3 h. Itwas then concentrated in vacuo to afford 16a. Crude 16a was diluted withmethanol (3 mL) and HBr solution (3 mL, 33% in acetic acid) at 0° C. Theresulting mixture was stirred for 10 min and the cooling bath wasremoved. The stirring was continued at room temperature overnight. Thesolution was concentrated and azeotroped with toluene and ethanol (10 mLeach) 3 times and purified by HPLC using a methanol/TFA solvent system.TFA was exchanged with HCl (6N aq., 10 ml×4) and lyophilized to obtain0.17 g of compound 41.

Example 3: Syntheses of Compound 43

To a solution of 14a (0.5 g, 0.62 mmol) in CH₂Cl₂ (5 mL) at 0° C. wereadded TEA (0.6 mL, 1.86 mmol) and MsCl (0.724 mL, 0.9 mmol). The mixturewas stirred for 3 h and then warmed up to room temperature and stirredfor an additional 1 h. It was then diluted with ice-cold water (10 mL)and brine (10 mL). The organic layer was separated and the aqueous layerwas extracted with additional CH₂Cl₂ (2×10 mL). The combined organiclayers were dried over sodium sulfate and concentrated to dryness to0.44 g of the mesylate. To this crude mesylate in EtOH (5 mL) was addedN,N′dimethyl thiourea (0.53 g, 4.5 mol) and the mixture stirred at 70°C. for 3 h. It was then concentrated in vacuo to afford 17a. Thiscompound was diluted with methanol (3 mL) and HBr solution (3 mL, 33% inacetic acid) at 0° C. This was stirred for 10 min and the cooling bathwas removed. The stirring was continued at room temperature overnight.The solution was concentrated and azeotroped with toluene and ethanol(10 mL each) for 3 times and purified by HPLC using a methanol-TFAsolvent system. TFA was fully exchanged with HCl (6N aq., 10 ml x 4) andlyophilized to obtain 0.15 g of compound 43.

Example 4: Syntheses of Compound 2

To a solution of 14a (0.8 g, 0.98 mmol) in CH₂Cl₂ (10 mL) at 0° C. wereadded TEA (0.6 mL, 1.86 mmol) and MsCl (1.4 mL, 1.2 mmol). The reactionwas stirred for 3 h, then warmed to ambient temperature and stirred foran additional 1 h. It was then diluted with ice-cold water (20 mL) andbrine (20 mL). The organic layer was separated and the aqueous layer wasextracted with additional CH₂Cl₂ (2×20 mL). The combined organic layerswere dried over sodium sulfate and concentrated to dryness to 0.88 g ofthe mesylate. To this crude mesylate in EtOH (10 mL) was addedimidazolidine-2-thione (0.25 g, 2.5 mol) and stirred at 70° C. for 3 h.It was then concentrated in vacuo to afford 18a (0.3 g). This compoundwas diluted with methanol (3 mL) and HBr solution (3 mL, 33% in aceticacid) at 0° C. This was stirred for 10 min and the cooling bath wasremoved. The stirring was continued at room temperature overnight. Thesolution was concentrated and azeotroped with toluene and ethanol (10 mLeach) 3 times and purified by HPLC using a methanol-TFA solvent system.TFA was fully exchanged with HCl (6N aq., 10 ml x 4) and lyophilized toobtain 0.103 g of compound 2.

Example 4: Syntheses of Compound 120

To a solution of 200 (800 mg, 935 umol, 1 eq) in tetrahydrofuran (10 mL)was added triethylamine (189 mg, 1.87 mmol, 2 eq) and compound 203 (200mg, 1.12 mmol, 1.2 eq). The reaction was stirred at room temperature for2 hours. Then ammonia (637 mg, 9.35 mmol, 624 uL, 25% purity, 10 eq) andmethanol (3 mL) was added to the reaction mixture. The reaction wasstirred at room temperature for 3 hours. On completion, the reactionmixture was concentrated in vacuum. The residue was purified by silicagel chromatography (Dichloromethane:Methanol=20:1) to give compound 201(250 mg, 27.6% yield) as a yellow solid. LCMS: m/z (M+H)⁺=878.3

To a solution of compound 201 (0.4 g, 456 umol, 1 eq) in methanol (10mL) was added methyl iodide (64 mg, 456 umol, 1 eq) at 0° C. Thereaction mixture was stirred at room temperature for 16 hours. Oncompletion, the reaction mixture was concentrated in vacuum and purifiedby silica gel chromatography (Dichloromethane:Methanol=50:1) to givecompound 202 (0.2 g, 49% yield) as a yellow solid. LCMS: m/z(M+H)⁺=892.2

To a solution of compound 202 (0.15 g, 168 umol, 1 eq) in methanol (4.5mL) was added hydrogen bromide (10.5 mL, 30% in acetic acid) at 0° C.The reaction was stirred at room temperature for 12 hours. Oncompletion, the reaction mixture was concentrated under vacuum to removethe solvents and the solid was dissolved in methanol (5.00 mL) and thenpurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.05% HCl)-ACN]; B %: 7%-37%, 10 min). Thesolution was lyophilized to give compound 120 (120, combined twobatches, 46.3% yield) as a yellow solid: LCMS: m/z (M+H)+=624.2.

Example 6—Antimicrobial Activity

The compounds of the present disclosure were tested for antimicrobialactivity. These data are presented in Table 2. The Compounds 1-122 wererun against Eschericia coli (E. coli) strain ATCC25922 and againstStaphylococcus aureus (S. aureus) 11540 strain using a standardmicrodilution assay to determine minimum inhibitory concentrations(MICs). The data is presented whereby a “+” indicates that the compoundhas an MIC value of 16 micrograms/mL or less and a “−” indicates thatthe compound has an MIC value greater than 16 micrograms/mL. It will berecognized by one skilled in the art that the compounds can be assessedagainst other bacterial organisms and that the presentation of data foractivity against Eschericia coli and Staphylococcus aureus areillustrative and in no way is intended to limit the scope of the presentdisclosure. The compounds of the present disclosure can be assayedagainst a range of other microorganisms depending upon the performanceactivity desired to be gathered. Furthermore, the “+” and “−”representation and the selection of a cutoff value of 16 micrograms/mLis also illustrative and in no way is intended to limit the scope of thepresent disclosure. For example, a “−” is not meant to indicate that thecompound necessarily lacks activity or utility, but rather that its MICvalue against the indicated microorganism is greater than 16micrograms/mL.

TABLE 2 MIC MIC # S. aureus E.coli 1 + + 2 + + 3 + + 4 + + 5 + + 6 + +7 + + 8 + + 9 + + 10 + + 11 + + 12 + + 13 + + 14 + + 15 + + 16 + +17 + + 18 + + 19 + + 20 + + 21 + + 22 + + 23 + + 24 + + 25 + + 26 + +27 + + 28 + + 29 + + 30 + + 31 + + 32 + + 33 + + 34 + + 35 + + 36 + +37 + + 38 + + 39 + + 40 + + 41 + + 42 + + 43 + + 44 + + 45 + + 46 + +47 + + 48 + + 49 + + 50 + + 51 + + 52 + + 53 + + 54 + + 55 + + 56 + +57 + + 58 + + 59 + + 60 + + 61 + + 62 + + 63 + + 64 + + 65 + + 66 + +67 + + 68 + + 69 + + 70 + + 71 + + 72 + + 73 + + 74 + + 75 + + 76 + + 77− + 78 + + 79 + + 80 + + 81 + + 82 + + 83 + + 84 + + 85 + + 86 + +87 + + 88 + + 89 + + 90 + + 91 + + 92 + + 93 + + 94 + + 95 + + 96 + +97 + − 98 + + 99 + + 100 + + 101 + + 102 + + 103 + + 104 + + 105 + +106 + + 107 + + 108 + + 109 + + 110 + + 111 + + 112 + + 113 + + 114 + +115 + − 116 + + 117 + + 118 + + 119 + + 120 + + 121 + + 122 + +

Example 7—Rat Infusion Study

Many pyrrolocytosines, including Compound No. 34, share an acuteclinical syndrome, which manifests in as a C_(max)-driven hemodynamiceffect and is associated with immediate clinical signs such as laboredbreathing. C_(max) is the peak concentration a molecule reaches in theplasma, in this case directly following intravenous administration, andis expressed generally in micrograms/milliliter. The syndrome isdose-dependent, meaning that the higher the amount of drug given, themore severe the effects. This is generally considered the limitingtoxicity for the effected compounds of this class. Importantly, theefficacy for the pyrrolocytosines, including Compound No. 34, is notdriven by the C_(max) but rather by the AUC(Area-Under-the-plasma-drug-concentration-time-Curve), which is anexpression of the total body exposure to the drug and is expressedgenerally in micrograms*hour/milliliter. In rat studies with severalpyrrolocytosines, including Compound No. 34, it has been shown thatincreasing the length, or duration, of the intravenous administrationeffectively modulates or eliminates the clinical syndrome, depresses theconcentration maximum, results in a short distribution half-life butstill affords drug exposures necessary for efficacy.

As an example, a study conducted by PharmOptima under study number2017-164 with Compound No. 34, compared the clinical signs and plasmadrug concentration data across several infusion lengths: 10-minutes,which is the screening length at which the acute syndrome is observed,1-hour, 2-hour, 3-hour and 24-hour. A total of 15 male Sprague-Dawleyrats (275-300 grams) were used in the study, divided evenly across the 5dosing regimens. The route of drug administration was via jugular venousinfusion, using a syringe infusion pump. Compound No. 34 was formulatedin phosphate-buffered mannitol, with a starting pH=6.5. Details of theinfusions and the plasma sample timepoints are given in Table 3.

TABLE 3 Details of Rat Infusion Periods Plasma timepoints, Test ArticleInfusion Infusion Volume in hours Group (dose) Duration rate delivered(0 h = infusion end) 1 (n = 3) 10 min 3 mL/10 min  3 mL 0, 0.083, 0.5,1, 2, 4, 6,   24, 48, 72, 96 2 (n = 3) Compound  1 h 1 mL/h  1 mL −0.25,0, 0.083, 0.5, 1, 2, No. 34 (4     4, 6, 24, 48, 72, 96 3 (n = 3) mg/kg) 2 h  2 mL −0.25, 0, 0.083, 0.5, 1, 2,     4, 6, 24, 48, 72, 96 4 (n =3)  3 h  3 mL −0.25, 0, 0.083, 0.5, 1, 2, 4, 6, 24, 48, 72, 96 5 (n = 3)24 h 24 mL −22, −20, −18, −1, −0.25, 0, 0.083, 0.5, 1, 2, 4, 6, 24, 48,72, 96

Table 4 shows the results. In the short 10-minute infusion, all threerats displayed signs of significant labored breathing; the 1 h, 2 h and3 h infusion groups only showed minor signs of chewing and licking, andthe 24 h infusion group showed no clinical signs. There was cleardecrease in C_(max) as infusion length was increased. The intermediatedosing groups still achieved significant AUC, or drug exposures forefficacy, and particularly with the 3 h infusion itis clear that thedose can be increased to move the AUC higher while not approaching theC_(max) associated with the severe end of the acute tolerability. The 24h infusion is particularly compelling. It indicates the concentrationcan be titrated to achieve steady-state drug levels for efficacy whileremaining well below the C_(max) associated with clinical signs.Furthermore, the alpha, or distribution-phase, half-life is short, whichindicates that—if clinical signs are observed—the infusion can bestopped and the plasma levels drop quickly. In the end, this translatesinto a generous therapeutic window.

TABLE 4 IV Plasma Pharmacokinetics of Compound No. 34 in MaleSprague-Dawley Rats (N = 3/infusion-group) IV Infusion 10-min 1 h 2 h 3h 24 h Clinical Signs significant labored chewing/licking none breathingCmax (μg/mL) 23.60 8.89 8.12 3.76 0.56 T½ (h)-terminal 15.19 15.17 T½(h)-alpha 1.01 0.91 1.02 0.99 1.01 AUCinf (μg/mL*h) 21.99 14.37 14.439.15 11.05

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The disclosure can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the disclosure described herein. Scope of thedisclosure is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A compound of Formula (AA):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: J is selected from

X is selected from a 5- or 6-membered heterocyclyl ring and phenyl,wherein each of the 5- or 6-membered heterocyclyl ring and phenyl isoptionally substituted with one or more R^(X); Z is selected from

R₁ is selected from H, C₁₋₃ alkyl, and C₂₋₄ alkenyl; R₂ is selected fromH and C₁₋₃ alkyl; R₃ is selected from H and C₁₋₃ alkyl; or R₂ and R₃together with the nitrogen atoms to which they are attached and thecarbon atom connecting the two nitrogen atoms form a 5- or 6-memberedring; or R₁ and R₃ together with the nitrogen and sulfur atom to whichthey are attached and the carbon atom connecting the two nitrogen atomsform a 5- or 6-membered ring; R₄ is selected from H and C₁₋₃ alkyl; R₅is selected from H and C₁₋₆ alkyl; R₆ is selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, OR^(a), SR^(a), —C(O)OR^(a), —SC(NH)NH₂, C₃₋₆cycloalkyl, and 3-6 membered heterocyclyl; R₇ is selected from H andC₁₋₆ alkyl; or R₆ and R₇ together with the carbon and nitrogen atoms towhich they are attached form a ring having one of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH; or R₅ and R₇ together with the carbon atoms to which they areattached and the nitrogen atom connecting the two carbon atoms form aring having one of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withOH; Q is selected from C₁₋₂ alkylene or —C(O)—; R₂₁ is selected from H,C₁₋₆ alkyl optionally substituted with 1-3 halo; R₈ is selected from Hand halogen; each R^(X) is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆cycloalkyl, and aryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more R^(b); or two adjacent R^(X) come together with theatoms to which they are attached to form a 5- or 6-membered ring; eachR^(a) is independently selected from H and C₁₋₆ alkyl; each R^(b) isindependently selected from C₂₋₆ alkenyl, OR^(c), N(R^(c))₂,—C(O)OR^(c), C₃₋₆ cycloalkyl, OC(NH)NH₂, and aryl; each R^(c) isindependently selected from H, C₁₋₆ alkyl, aryl, —C(O)aryl, and—(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are each optionallysubstituted with one or more R^(d); and each R^(d) is independentlyselected from C₁₋₃ alkyl, OH, O(C₁₋₃ alkyl), NO₂, NH₂, NH(C₁₋₃ alkyl),and N(C₁₋₃ alkyl)₂; or a compound of Formula (A):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: X is selected from a 5- or 6-memberedheterocyclyl ring and phenyl, wherein each of the 5- or 6-memberedheterocyclyl ring and phenyl is optionally substituted with one or moreR^(X); Z is selected from

R₁ is selected from H and C₁₋₃ alkyl; R₂ is selected from H and C₁₋₃alkyl; R₃ is selected from H and C₁₋₃ alkyl; or R₂ and R₃ together withthe nitrogen atoms to which they are attached and the carbon atomconnecting the two nitrogen atoms form a 5- or 6-membered ring; R₄ isselected from H and C₁₋₃ alkyl; R₅ is selected from H and C₁₋₆ alkyl; R₆is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆ alkylis optionally substituted with one or more substituents selected fromthe group consisting of halogen, OR^(a), SR^(a), —C(O)OR^(a),—SC(NH)NH₂, C₃₋₆ cycloalkyl, and 3-6 membered heterocyclyl; R₇ isselected from H and C₁₋₆ alkyl; or R₆ and R₇ together with the carbonand nitrogen atoms to which they are attached form a ring having one ofthe formulas:

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH; or R₅ and R₇ together with the carbon atoms to which they areattached and the nitrogen atom connecting the two carbon atoms form aring having one of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withOH; Q is selected from C₁₋₂ alkylene or —C(O)—; R₂₁ is selected from H,C₁₋₆ alkyl optionally substituted with 1-3 halo; R₈ is selected from Hand halogen; each R^(X) is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆cycloalkyl, and aryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more R^(b); or two adjacent R_(X) come together with theatoms to which they are attached to form a 5- or 6-membered ring; eachR^(a) is independently selected from H and C₁₋₆ alkyl; each R^(b) isindependently selected from C₂₋₆ alkenyl, OR^(c), N(R^(c))₂,—C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl; each R^(c) is independentlyselected from H, C₁₋₆ alkyl, aryl, —C(O)aryl, and —(CH₂)aryl, whereinthe C₁₋₆ alkyl and the aryl are each optionally substituted with one ormore R^(d); and each R^(d) is independently selected from C₁₋₃ alkyl,OH, O(C₁₋₃ alkyl), NO₂, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂; or acompound of Formula (I)

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: X is selected from a 5- or 6-memberedheterocyclyl ring and phenyl, wherein each of the 5- or 6-memberedheterocyclyl ring and phenyl is optionally substituted with one or moreR^(X); R₁ is selected from Hand C₁₋₃ alkyl; R₂ is selected from HandC₁₋₃alkyl; R₃ is selected from Hand C₁₋₃alkyl; or R₂ and R₃ togetherwith the nitrogen atoms to which they are attached and the carbon atomconnecting the two nitrogen atoms form a 5- or 6-membered ring; R₄ isselected from Hand C₁₋₃alkyl; R₅ is selected from Hand C₁₋₆alkyl; R₆ isselected from H, C₁₋₆alkyl, and C₂₋₆ alkenyl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents selected from thegroup consisting of halogen, OR^(a), SR^(a), —C(O)OR^(a), —SC(NH)NH₂,C₃₋₆cycloalkyl, and 3-6 membered heterocyclyl; R₇ is selected from H andC₁₋₆alkyl; or R₆ and R₇ together with the carbon and nitrogen atoms towhich they are attached form a ring having one of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH; or R₅ and R₇ together with the carbon atoms to which they areattached and the nitrogen atom connecting the two carbon atoms form aring having one of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withOH; R₈ is selected from H and halogen; each R^(X) is independentlyselected from halogen, C₁₋₆ alkyl, C₁₋₄ haloalkyl, OR^(c), N(R^(c))₂,—C(O)OR^(c), —C(O)R^(c), C₃₋₆ cycloalkyl, and aryl, wherein the C₁₋₆alkyl is optionally substituted with one or more R^(b); or two adjacentR^(X) come together with the atoms to which they are attached to form a5- or 6-membered ring; each R^(a) is independently selected from H andC₁₋₆ alkyl; each R^(b) is independently selected from C₂₋₆ alkenyl,OR^(c), N(R^(c))₂, —C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl; each R^(c) isindependently selected from H, C₁₋₆ alkyl, aryl, —C(O)aryl, and—(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl are each optionallysubstituted with one or more R^(d); and each R^(d) is independentlyselected from C₁₋₃ alkyl, OH, O(C₁₋₃ alkyl), NO₂, NH₂, NH(C₁₋₃ alkyl),and N(C₁₋₃ alkyl)₂.
 2. The compound of claim 1, wherein each of R₁, R₂,and R₃ is H.
 3. The compound of claim 1, wherein two of R₁, R₂, and R₃are H, and the other is C₁₋₃ alkyl.
 4. The compound of any one of claims1 and 2, wherein two of R₁, R₂, and R₃ are H, and the other is methyl.5. The compound of claim 1, wherein one of R₁, R₂, and R₃ is H, and theother two are C₁₋₃ alkyl.
 6. The compound of any one of claims 1 and 5,wherein one of R₁, R₂, and R₃ is H, and the other two are methyl.
 7. Thecompound of claim 1, wherein R₁ is H; and R₂ and R₃ together with thenitrogen atoms to which they are attached and the carbon atom connectingthe two nitrogen atoms form a 5- or 6-membered ring.
 8. The compound ofclaim 1, wherein R₁ is H; and R₂ and R₃ together with the nitrogen atomsto which they are attached and the carbon atom connecting the twonitrogen atoms form an imidazoline.
 9. The compound of any one of claims1-8, wherein R₄ is H.
 10. The compound of any one of claims 1-8, whereinR₄ is C₁₋₃ alkyl.
 11. The compound of any one of claims 1-10, whereinone of R₅ and R₇ is H and the other is C₁₋₆ alkyl.
 12. The compound ofany one of claims 1-11, wherein R₅ is H and R₇ is C₁₋₆ alkyl.
 13. Thecompound of any one of claims 1-10, wherein R₅ and R₇ together with thecarbon atoms to which they are attached and the nitrogen atom connectingthe two carbon atoms form


14. The compound of any one of claims 1-10, wherein R₅ and R₇ togetherwith the carbon atoms to which they are attached and the nitrogen atomconnecting the two carbon atoms form

wherein the ring is optionally substituted with C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is optionally substituted with one or more OH.
 15. Thecompound of any one of claims 1-10, wherein R₅ and R₇ together with thecarbon atoms to which they are attached and the nitrogen atom connectingthe two carbon atoms form


16. The compound of any one of claims 1-10, wherein R₅ and R₇ togetherwith the carbon atoms to which they are attached and the nitrogen atomconnecting the two carbon atoms form


17. The compound of any one of claims 1-10, wherein R₆ and R₇ togetherwith the carbon and nitrogen atoms to which they are attached form aring of formula


18. The compound of any one of claims 1-10, wherein R₆ and R₇ togetherwith the carbon and nitrogen atoms to which they are attached form aring of formula


19. The compound of any one of claims 1-16, wherein R₆ is selected fromH and C₁₋₆ alkyl optionally substituted with one or more substituentsselected from the group consisting of halogen and OR^(a).
 20. Thecompound of any one of claims 1-19, wherein R₆ is H.
 21. The compound ofany one of claims 1-19, wherein R₆ is C₁₋₆ alkyl optionally substitutedwith one or more substituents selected from the group consisting ofhalogen and OR^(a).
 22. The compound of any one of claims 1-19 and 21,wherein R₆ is C₁₋₆ alkyl optionally substituted with OR^(a).
 23. Thecompound of any one of claims 1-19, 21, and 22, wherein R^(a) is H. 24.The compound of any one of claims 1-19, 21, and 22, wherein R^(a) isC₁₋₆ alkyl.
 25. The compound of any one of claims 1-19, 21, and 22,wherein R₆ is C₁₋₆ alkyl substituted with —SC(NH)NH₂.
 26. The compoundof any one of claims 1-16, wherein R₆ is C₁₋₆ alkyl optionallysubstituted with halogen.
 27. The compound of any one of claims 1-16 and26, wherein R₆ is C₁₋₆ alkyl optionally substituted with fluoro.
 28. Thecompound of any one of claims 1-27, wherein X is selected from a5-membered heterocyclyl ring and phenyl, wherein each of the 5-memberedheterocyclyl ring and phenyl is optionally substituted with one or moreR^(X).
 29. The compound of any one of claims 1-28, wherein X is a5-membered heterocyclyl ring optionally substituted with one or moreR^(X).
 30. The compound of any one of claims 1-29, wherein X is apyrrolidinyl optionally substituted with one or more R^(X).
 31. Thecompound of any one of claims 1-30, wherein X is a 2- or 3-pyrrolidinyloptionally substituted with one or more R^(X).
 32. The compound of anyone of claims 1-28, wherein X is phenyl optionally substituted with oneor more R^(X).
 33. The compound of any one of claims 1-28 and 32,wherein X is phenyl optionally substituted with three R^(X).
 34. Thecompound of any one of claims 1-33, wherein R^(X) is independentlyselected from halogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c),—C(O)R^(c), C₃₋₆ cycloalkyl, and aryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more R^(b).
 35. The compound of anyone of claims 1-34, wherein R^(X) is independently selected from halogenand C₁₋₆ alkyl optionally substituted with one or more R^(b).
 36. Thecompound of any one of claims 1-35, wherein R^(b) is selected from C₂₋₆alkenyl, OR^(c), N(R^(c))₂, and C₃₋₆ cycloalkyl.
 37. The compound of anyone of claims 1-36, wherein R^(b) is selected from C₂₋₆ alkenyl, OR^(c),NH₂, and cyclopropyl.
 38. The compound of any one of claims 1-37,wherein R^(c) is selected from H and C₁₋₆ alkyl.
 39. The compound of anyone of claims 1-37, wherein R^(b) is selected from vinyl, OH, and NH₂.40. The compound of any one of claims 1-39, wherein two adjacent R^(X)come together with the atoms to which they are attached to form a 5- or6-membered ring.
 41. A compound of Formula (IA):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: X is selected from a 5- or 6-memberedheterocyclyl ring and phenyl, wherein each of the 5- or 6-memberedheterocyclyl ring and phenyl is optionally substituted with one or moreR^(X); R₁ is selected from H and C₁₋₃ alkyl; R₂ is selected from H andC₁₋₃ alkyl; R₃ is selected from H and C₁₋₃ alkyl; R₄ is selected from Hand C₁₋₃ alkyl; R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆ alkenyl,wherein the C₁₋₆ alkyl is optionally substituted with one or moresubstituents selected from the group consisting of halogen, OR^(a),SR^(a), —C(O)OR^(a), —SC(NH)NH₂, C₃₋₆ cycloalkyl, or C₃₋₆ heterocyclyl;each R^(X) is independently selected from halogen, C₁₋₆ alkyl, C₁₋₄haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆ cycloalkyl,and aryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore R^(b); or two adjacent R^(X) come together with the atoms to whichthey are attached to form a 5- or 6-membered ring; each R^(a) isindependently selected from H and C₁₋₆ alkyl; each R^(b) isindependently selected from C₂₋₆ alkenyl, OR^(c), N(R^(c))₂,—C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl; each R^(c) is independentlyselected from H, C₁₋₆ alkyl, aryl, —C(O)aryl, and —(CH₂)aryl, whereinthe C₁₋₆ alkyl and the aryl are each optionally substituted with one ormore R^(d); and each R^(d) is independently selected from C₁₋₃ alkyl,OH, O(C₁₋₃ alkyl), NO₂, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.
 42. Thecompound of claim 41, wherein each of R₁, R₂, and R₃ is H.
 43. Thecompound of claim 41, wherein two of R₁, R₂, and R₃ are H, and the otheris C₁₋₃ alkyl.
 44. The compound of any one of claims 41 and 42, whereintwo of R₁, R₂, and R₃ are H, and the other is methyl.
 45. The compoundof claim 41, wherein one of R₁, R₂, and R₃ is H, and the other two areC₁₋₃ alkyl.
 46. The compound of any one of claims 41 and 45, wherein oneof R₁, R₂, and R₃ is H, and the other two are methyl.
 47. The compoundof claim 41, wherein R₂ and R₃ together with the nitrogen atoms to whichthey are attached and the carbon atom connecting the two nitrogen atomsform a 5- or 6-membered ring.
 48. The compound of claim 41, wherein R₂and R₃ together with the nitrogen atoms to which they are attached andthe carbon atom connecting the two nitrogen atoms form an imidazoline.49. The compound of any one of claims 41-48, wherein R₄ is H.
 50. Thecompound of any one of claims 41-48, wherein R₄ is C₁₋₃ alkyl.
 51. Thecompound of any one of claims 41-50, wherein R₆ is selected from H andC₁₋₆ alkyl optionally substituted with one or more substituents selectedfrom the group consisting of halogen and OR.
 52. The compound of any oneof claims 41-51, wherein R₆ is H.
 53. The compound of any one of claims41-51, wherein R₆ is C₁₋₆ alkyl optionally substituted with one or moresubstituents selected from the group consisting of halogen and OR^(a).54. The compound of any one of claims 41-51 and 53, wherein R₆ is C₁₋₆alkyl optionally substituted with OR^(a).
 55. The compound of any one ofclaims 41-51, 53, and 54, wherein R^(a) is H.
 56. The compound of anyone of claims 41-51, 53, and 54, wherein R^(a) is C₁₋₆ alkyl.
 57. Thecompound of any one of claims 41-50, wherein R₆ is C₁₋₆ alkylsubstituted with —SC(NH)NH₂.
 58. The compound of any one of claims41-50, wherein R₆ is C₁₋₆ alkyl optionally substituted with halogen. 59.The compound of any one of claims 41-50 and 58, wherein R₆ is C₁₋₆ alkyloptionally substituted with fluoro.
 60. The compound of any one ofclaims 41-59, wherein X is selected from a 5-membered heterocyclyl ringand phenyl, wherein each of the 5-membered heterocyclyl ring and phenylis optionally substituted with one or more R^(X).
 61. The compound ofany one of claims 41-60, wherein X is a 5-membered heterocyclyl ringoptionally substituted with one or more R^(X).
 62. The compound of anyone of claims 41-61, wherein X is a pyrrolidinyl optionally substitutedwith one or more R^(X).
 63. The compound of any one of claims 41-62,wherein X is a 2- or 3-pyrrolidinyl optionally substituted with one ormore R^(X).
 64. The compound of any one of claims 41-60, wherein X isphenyl optionally substituted with one or more R^(X).
 65. The compoundof any one of claims 41-60 and 64, wherein X is phenyl optionallysubstituted with three R^(X).
 66. The compound of any one of claims41-65, wherein R^(X) is independently selected from halogen, C₁₋₆ alkyl,OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆ cycloalkyl, and aryl,wherein the C₁₋₆ alkyl is optionally substituted with one or more R^(b).67. The compound of any one of claims 41-66, wherein R^(X) isindependently selected from halogen and C₁₋₆ alkyl optionallysubstituted with one or more R^(b).
 68. The compound of any one ofclaims 41-66, wherein R^(b) is selected from C₂₋₆ alkenyl, OR^(c),N(R^(c))₂, and C₃₋₆ cycloalkyl.
 69. The compound of any one of claims41-66 and 68, wherein R^(b) is selected from C₂₋₆ alkenyl, OR^(c), NH₂,and cyclopropyl.
 70. The compound of claim 69, wherein R^(c) is selectedfrom H and C₁₋₆ alkyl.
 71. The compound of claim 69, wherein R^(b) isselected from vinyl, OH, and NH₂.
 72. The compound of any one of claims41-71, wherein two adjacent R^(X) come together with the atoms to whichthey are attached to form a 5- or 6-membered ring.
 73. A compound ofFormula (IB):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: X is selected from a 5- or 6-memberedheterocyclyl ring and phenyl, wherein each of the 5- or 6-memberedheterocyclyl ring and phenyl is optionally substituted with one or moreR^(X); each R^(X) is independently selected from halogen, C₁₋₆ alkyl,C₁₋₄ haloalkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c), —C(O)R^(c), C₃₋₆cycloalkyl, and aryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more R^(b); or two adjacent R^(X) come together with theatoms to which they are attached to form a 5- or 6-membered ring; eachR^(b) is independently selected from C₂₋₆ alkenyl, OR^(c), N(R^(c))₂,—C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl; each R^(c) is independentlyselected from H, C₁₋₆ alkyl, aryl, —C(O)aryl, and —(CH₂)aryl, whereinthe C₁₋₆ alkyl and the aryl are each optionally substituted with one ormore R^(d); and each R^(d) is independently selected from C₁₋₃ alkyl,OH, O(C₁₋₃ alkyl), NO₂, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.
 74. Thecompound of claim 73, wherein X is selected from a 5-memberedheterocyclyl ring and phenyl, wherein each of the 5-memberedheterocyclyl ring and phenyl is optionally substituted with one or moreR^(X).
 75. The compound of any one of claims 73 and 74, wherein X is a5-membered heterocyclyl ring optionally substituted with one or moreR^(X).
 76. The compound of any one of claims 73-75, wherein X is apyrrolidinyl optionally substituted with one or more R^(X).
 77. Thecompound of any one of claims 73-76, wherein X is a 2- or 3-pyrrolidinyloptionally substituted with one or more R^(X).
 78. The compound of anyone of claims 73 and 74, wherein X is phenyl optionally substituted withone or more R_(X).
 79. The compound of any one of claims 73, 74, and 78,wherein X is phenyl optionally substituted with three R^(X).
 80. Thecompound of any one of claims 73-79, wherein R^(X) is independentlyselected from halogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂, —C(O)OR^(c),—C(O)R^(c), C₃₋₆ cycloalkyl, and aryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more R^(b).
 81. The compound of anyone of claims 73-79, wherein R^(X) is independently selected fromhalogen and C₁₋₆ alkyl optionally substituted with one or more R^(b).82. The compound of claim 81, wherein R^(b) is selected from C₂₋₆alkenyl, OR^(c), N(R^(c))₂, and C₃₋₆ cycloalkyl.
 83. The compound of anyone of claims 81 and 82, wherein R^(b) is selected from C₂₋₆ alkenyl,OR^(c), NH₂, and cyclopropyl.
 84. The compound of any one of claims73-83, wherein R^(c) is selected from H and C₁₋₆ alkyl.
 85. The compoundof any one of claims 81-83, wherein R^(b) is selected from vinyl, OH,and NH₂.
 86. The compound of any one of claims 73-85, wherein twoadjacent R^(X) come together with the atoms to which they are attachedto form a 5- or 6-membered ring.
 87. A compound of Formula (II):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: R₁ is selected from H and C₁₋₃ alkyl; R₂is selected from H and C₁₋₃ alkyl; R₃ is selected from H and C₁₋₃ alkyl;or R₂ and R₃ together with the nitrogen atoms to which they are attachedand the carbon atom connecting the two nitrogen atoms form a 5- or6-membered ring; R₄ is selected from H and C₁₋₃ alkyl; R₅ is selectedfrom H and C₁₋₆ alkyl; R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents selected from the group consisting of halogen, OR^(a),SR^(a), —C(O)OR^(a), —SC(NH)NH₂, C₃₋₆ cycloalkyl, or C₃₋₆ heterocyclyl;R₇ is selected from H and C₁₋₆ alkyl; or R₆ and R₇ together with thecarbon and nitrogen atoms to which they are attached form a ring havingone of the formulas:

wherein the ring is optionally substituted on a ring carbon atom withC₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore OH; or R₅ and R₇ together with the carbon atoms to which they areattached and the nitrogen atom connecting the two carbon atoms form aring having one of the formulas:

R₈ is selected from H and halogen; R₉ is selected from H and halogen;R₁₀ is selected from H, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₆cycloalkyl; R₁₁ is selected from C₁₋₃ alkyl, C₂₋₄ alkenyl, and C₃₋₆cycloalkyl, wherein the C₁₋₃ alkyl is optionally substituted with one ormore R^(b); R₁₇ is selected from H, halogen, and C₁₋₆ alkyl; each R^(a)is independently selected from H and C₁₋₆ alkyl; each R^(b) isindependently selected from OR^(c), —C(O)OR^(c), and —(O)aryl, whereinthe aryl is optionally substituted with one or more R^(d); each R^(c) isindependently selected from hydrogen, C₁₋₃ alkyl, OH, O(C₁₋₃ alkyl),NO₂, —C(O)aryl, and aryl; and each R^(d) is C₁₋₃ alkyl.
 88. The compoundof claim 87, wherein each of R₁, R₂, and R₃ is H.
 89. The compound ofclaim 87, wherein two of R₁, R₂, and R₃ are H, and the other is C₁₋₃alkyl.
 90. The compound of any one of claims 87 and 89, wherein two ofR₁, R₂, and R₃ are H, and the other is methyl.
 91. The compound of claim87, wherein one of R₁, R₂, and R₃ is H, and the other two are C₁₋₃alkyl.
 92. The compound of any one of claims 87 and 91, wherein one ofR₁, R₂, and R₃ is H, and the other two are methyl.
 93. The compound ofclaim 87, wherein R₂ and R₃ together with the nitrogen atoms to whichthey are attached and the carbon atom connecting the two nitrogen atomsform a 5- or 6-membered ring.
 94. The compound of any one of claim 87 or93, wherein R₂ and R₃ together with the nitrogen atoms to which they areattached and the carbon atom connecting the two nitrogen atoms form animidazoline.
 95. The compound of any one of claims 87-94, wherein R₄ isH.
 96. The compound of any one of claims 87-94, wherein R₄ is C₁₋₃alkyl.
 97. The compound of any one of claims 87-96, wherein one of R₅and R₇ is H and the other is C₁₋₆ alkyl.
 98. The compound of any one ofclaims 87-97, wherein R₅ is H and R₇ is C₁₋₆ alkyl.
 99. The compound ofany one of claims 87-96, wherein R₅ and R₇ together with the carbonatoms to which they are attached and the nitrogen atom connecting thetwo carbon atoms form


100. The compound of any one of claims 87-96, wherein R₅ and R₇ togetherwith the carbon atoms to which they are attached and the nitrogen atomconnecting the two carbon atoms form

wherein the ring is optionally substituted with C₁₋₆ alkyl, wherein theC₁₋₆ alkyl is optionally substituted with one or more OH.
 101. Thecompound of any one of claims 87-96, wherein R₅ and R₇ together with thecarbon atoms to which they are attached and the nitrogen atom connectingthe two carbon atoms form


102. The compound of any one of claims 87-96, wherein R₅ and R₇ togetherwith the carbon atoms to which they are attached and the nitrogen atomconnecting the two carbon atoms form


103. The compound of any one of claims 87-96, wherein R₆ and R₇ togetherwith the carbon and nitrogen atoms to which they are attached form aring of formula


104. The compound of any one of claims 87-96, wherein R₆ and R₇ togetherwith the carbon and nitrogen atoms to which they are attached form aring of formula


105. The compound of any one of claims 87-102, wherein R₆ is selectedfrom H and C₁₋₆ alkyl optionally substituted with one or moresubstituents selected from the group consisting of halogen and OR. 106.The compound of any one of claims 87-102 and 105, wherein R₆ is H. 107.The compound of any one of claims 87-102 and 105, wherein R₆ is C₁₋₆alkyl optionally substituted with one or more substituents selected fromthe group consisting of halogen and OR^(a).
 108. The compound of any oneof claims 87-102, 105, and 107, wherein R₆ is C₁₋₆ alkyl optionallysubstituted with OR.
 109. The compound of any one of claims 87-105, 107,and 108, wherein R^(a) is H.
 110. The compound of any one of claims87-105, 107, and 108, wherein R^(a) is C₁₋₆ alkyl.
 111. The compound ofany one of claims 87-102, wherein R₆ is C₁₋₆ alkyl substituted with—SC(NH)NH₂.
 112. The compound of any one of claims 87-102, 105, and 107,wherein R₆ is C₁₋₆ alkyl optionally substituted with halogen.
 113. Thecompound of any one of claims 87-102, 105, 107, and 112, wherein R₆ isC₁₋₆ alkyl optionally substituted with fluoro.
 114. The compound of anyone of claims 87-113, wherein R₈ is H.
 115. The compound of any one ofclaims 87-114, wherein one of R₉ and R₁₀ is halogen and the other is H.116. The compound of any one of claims 87-114, wherein each of R₉ andR₁₀ is halogen.
 117. The compound of any one of claims 87-114 and 116,wherein R₉ is fluoro and R₁₀ is chloro.
 118. The compound of any one ofclaims 87-114, wherein R₉ is H and R₁₀ is C₁₋₄ alkyl.
 119. The compoundof any one of claims 87-114, wherein R₉ is halogen and R₁₀ is C₁₋₄alkyl.
 120. The compound of any one of claims 87-114 and 119, wherein R₉is chloro and R₁₀ is C₁₋₄ alkyl.
 121. The compound of any one of claims87-114 and 119, wherein R₉ is fluoro and R₁₀ is C₁₋₄ alkyl.
 122. Thecompound of any one of claims 87-114 and 118-121, wherein R₁₀ is ethyl.123. The compound of any one of claims 87-114 and 118-121, wherein R₁₀is isopropyl.
 124. The compound of any one of claims 87-114, wherein R₉is H and R₁₀ is C₃₋₆ cycloalkyl.
 125. The compound of any one of claims87-114 and 124, wherein R₁₀ is cyclopropyl.
 126. The compound of any oneof claims 87-114 and 124, wherein R₁₀ is cyclopentyl.
 127. The compoundof any one of claims 87-126, wherein R₁₁ is selected from C₁₋₃ alkyloptionally substituted with one or more R, and C₂₋₄ alkenyl.
 128. Thecompound of any one of claims 87-126, wherein R₁₁ is selected from C₁₋₃alkyl optionally substituted with one or more R, and C₃₋₆ cycloalkyl.129. The compound of any one of claims 87-128, wherein R₁₁ is C₁₋₃ alkyloptionally substituted with one or more R^(b).
 130. The compound of anyone of claims 127-129, wherein R^(b) is OR^(c), and wherein R^(c) isselected from H and C₁₋₃ alkyl.
 131. The compound of claim 130, whereinR^(c) is H.
 132. The compound of claim 130, wherein R^(c) is C₁₋₃ alkyl.133. The compound of any one of claims 87-129, wherein R₁₁ is C₁₋₃alkyl.
 134. The compound of any one of claims 87-129 and 133, whereinR₁₁ is methyl.
 135. The compound of any one of claims 87-126 and 128,wherein R₁₁ is C₃₋₆ cycloalkyl.
 136. The compound of any one of claims87-126, 128, and 135, wherein R₁₁ is cyclopropyl.
 137. The compound ofany one of claims 87-136, wherein the Cahn-Ingold-Prelog configurationat the carbon atom R₁₁ is bonded to is (R).
 138. The compound of any oneof claims 87-137, wherein the Cahn-Ingold-Prelog configuration at thecarbon atom R₁₁ is bonded to is (S).
 139. The compound of any one ofclaims 87-138, wherein R₁₇ is H.
 140. The compound of any one of claims87-138, wherein R₁₇ is halogen.
 141. The compound of any one of claims87-114, 116, 129, and 137-140, wherein each of R₉ and R₁₀ is halogen,and R₁₁ is C₁₋₃ alkyl optionally substituted with one or more R^(b).142. The compound of claim 141, wherein R₉ is fluoro, R₁₀ is chloro, andR₁₁ is C₁₋₃ alkyl optionally substituted with one or more R^(b). 143.The compound of claim 142, wherein R₉ is fluoro, R₁₀ is chloro, and R₁₁is methyl.
 144. The compound of claim 143, wherein R₉ is fluoro, R₁₀ ischloro, R₁₁ is methyl, and wherein the Cahn-Ingold-Prelog configurationat the carbon atom R₁₁ is bonded to is (S).
 145. The compound of any oneof claims 87, 97-102, 114, 139, and 140, wherein each of R₁, R₂, and R₃is H; R₄ is H; R₆ is C₁₋₆ alkyl optionally substituted with one or moresubstituents selected from the group consisting of halogen and OR^(a);R₉ is fluoro, R₁₀ is chloro, and R₁₁ is methyl.
 146. The compound of anyone of claims 87, 97-102, 114, 139, and 140, wherein each of R₁, R₂, andR₃ is H; R₄ is H; R₆ is H or C₁₋₆ alkyl; R₉ is fluoro, R₁₀ is chloro,R₁₁ is methyl, and wherein the Cahn-Ingold-Prelog configuration at thecarbon atom R₁₁ is bonded to is (S).
 147. The compound of any one ofclaims 87, 114, 139, and 140, wherein each of R₁, R₂, and R₃ is H; R₄ isH; R₆ and R₇ together with the carbon and nitrogen atoms to which theyare attached form a ring of formula

R₉ is fluoro; R₁₀ is chloro; and R₁₁ is methyl.
 148. The compound of anyone of claims 87, 114, 139, and 140, wherein each of R₁, R₂, and R₃ isH; R₄ is H; R₅ and R₇ together with the carbon atoms to which they areattached and the nitrogen atom connecting the two carbon atoms form

R₆; R₆ is H or C₁₋₆ alkyl; R₉ is fluoro, R₁₀ is chloro, R₁₁ is methyl,and wherein the Cahn-Ingold-Prelog configuration at the carbon atom R₁₁is bonded to is (S).
 149. A compound of Formula (IIA):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: R₁ is selected from H and C₁₋₃ alkyl; R₂is selected from H and C₁₋₃ alkyl; R₃ is selected from H and C₁₋₃ alkyl;R₄ is selected from H and C₁₋₃ alkyl; R₆ is selected from H, C₁₋₆ alkyl,and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionally substituted withone or more substituents selected from the group consisting of halogenand OR^(a); R₉ is selected from H and halogen; R₁₀ is selected from H,halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₆ cycloalkyl R₁₁ is selectedfrom C₁₋₃ alkyl, C₂₋₄ alkenyl, and C₃₋₆ cycloalkyl, wherein the C₁₋₃alkyl is optionally substituted with one or more R^(b); each R^(a) isindependently selected from H and C₁₋₆ alkyl; each R^(b) isindependently selected from OR^(c), —C(O)OR^(c), and —(O)aryl, whereinthe aryl is optionally substituted with one or more R^(d); each R^(c) isindependently selected from hydrogen, C₁₋₃ alkyl, OH, O(C₁₋₃ alkyl),NO₂, —C(O)aryl, and aryl; and each R^(d) is C₁₋₃ alkyl.
 150. Thecompound of claim 149, wherein each of R₁, R₂, and R₃ is H.
 151. Thecompound of claim 149, wherein two of R₁, R₂, and R₃ are H, and theother is C₁₋₃ alkyl.
 152. The compound of any one of claims 149 and 151,wherein two of R₁, R₂, and R₃ are H, and the other is methyl.
 153. Thecompound of claim 149, wherein one of R₁, R₂, and R₃ is H, and the othertwo are C₁₋₃ alkyl.
 154. The compound of any one of claims 149 and 153,wherein one of R₁, R₂, and R₃ is H, and the other two are methyl. 155.The compound of claim 149, wherein R₂ and R₃ together with the nitrogenatoms to which they are attached and the carbon atom connecting the twonitrogen atoms form a 5- or 6-membered ring.
 156. The compound of anyone of claims 149 and 155, wherein R₂ and R₃ together with the nitrogenatoms to which they are attached and the carbon atom connecting the twonitrogen atoms form an imidazoline.
 157. The compound of any one ofclaims 149-156, wherein R₄ is H.
 158. The compound of any one of claims149-156, wherein R₆ is selected from H and C₁₋₆ alkyl optionallysubstituted with one or more substituents selected from the groupconsisting of halogen and OR.
 159. The compound of any one of claims149-158, wherein R₆ is H.
 160. The compound of any one of claims149-158, wherein R₆ is C₁₋₆ alkyl optionally substituted with one ormore substituents selected from the group consisting of halogen andOR^(a).
 161. The compound of any one of claims 149-158 and 160, whereinR₆ is C₁₋₆ alkyl optionally substituted with OR^(a).
 162. The compoundof any one of claims 149-158 and 160-161, wherein R^(a) is H.
 163. Thecompound of any one of claims 149-158 and 160-161, wherein R^(a) is C₁₋₆alkyl.
 164. The compound of any one of claims 149-158 and 160, whereinR₆ is C₁₋₆ alkyl optionally substituted with halogen.
 165. The compoundof any one of claims 149-158, 160, and 164, wherein R₆ is C₁₋₆ alkyloptionally substituted with fluoro.
 166. The compound of any one ofclaims 149-165, wherein one of R₉ and R₁₀ is halogen and the other is H.167. The compound of any one of claims 149-165, wherein each of R₉ andR₁₀ is halogen.
 168. The compound of any one of claims 149-165 and 167,wherein R₉ is fluoro and R₁₀ is chloro.
 169. The compound of any one ofclaims 149-165, wherein R₉ is H and R₁₀ is C₁₋₄ alkyl.
 170. The compoundof any one of claims 149-165, wherein R₉ is halogen and R₁₀ is C₁₋₄alkyl.
 171. The compound of any one of claims 149-165 and 170, whereinR₉ is chloro and R₁₀ is C₁₋₄ alkyl.
 172. The compound of any one ofclaims 149-165 and 170, wherein R₉ is fluoro and R₁₀ is C₁₋₄ alkyl. 173.The compound of any one of claims 149-165 and 169-172, wherein R₁₀ isethyl.
 174. The compound of any one of claims 149-165 and 169-172,wherein R₁₀ is isopropyl.
 175. The compound of any one of claims149-165, wherein R₉ is H and R₁₀ is C₃₋₆ cycloalkyl.
 176. The compoundof any one of claims 149-165 and 175, wherein R₁₀ is cyclopropyl. 177.The compound of any one of claims 149-165 and 175, wherein R₁₀ iscyclopentyl.
 178. The compound of any one of claims 149-177, wherein R₁₁is selected from C₁₋₃ alkyl optionally substituted with one or moreR^(b), and C₂₋₄ alkenyl.
 179. The compound of any one of claims 149-177,wherein R₁₁ is selected from C₁₋₃ alkyl optionally substituted with oneor more R^(b), and C₃₋₆ cycloalkyl.
 180. The compound of any one ofclaims 149-179, wherein R₁₁ is C₁₋₃ alkyl optionally substituted withone or more R^(b).
 181. The compound of any one of claims 178-180,wherein R^(b) is OR^(c), and wherein R^(c) is selected from H and C₁₋₃alkyl.
 182. The compound of claim 181, wherein R^(c) is H.
 183. Thecompound of claim 181, wherein R^(c) is C₁₋₃ alkyl.
 184. The compound ofany one of claims 149-179, wherein R₁₁ is C₁₋₃ alkyl.
 185. The compoundof any one of claims 149-179 and 184, wherein R₁₁ is methyl.
 186. Thecompound of any one of claims 149-177 and 179, wherein R₁₁ is C₃₋₆cycloalkyl.
 187. The compound of any one of claims 149-177, 179, and186, wherein R₁₁ is cyclopropyl.
 188. The compound of any one of claims149-187, wherein the Cahn-Ingold-Prelog configuration at the carbon atomR₁₁ is bonded to is (R).
 189. The compound of any one of claims 149-188,wherein the Cahn-Ingold-Prelog configuration at the carbon atom R₁₁ isbonded to is (S).
 190. The compound of any one of claims 149-165,wherein each of R₉ and R₁₀ is halogen, and R₁₁ is C₁₋₃ alkyl optionallysubstituted with one or more R^(b).
 191. The compound of any one ofclaims 149-165 and 190, wherein R₉ is fluoro, R₁₀ is chloro, and R₁₁ isC₁₋₃ alkyl optionally substituted with one or more R^(b).
 192. Thecompound of any one of claims 149-165, 190, and 191, wherein R₉ isfluoro, R₁₀ is chloro, and R₁₁ is methyl.
 193. The compound of any oneof claims 149-165 and 190-192, wherein R₉ is fluoro, R₁₀ is chloro, R₁₁is methyl, and wherein the Cahn-Ingold-Prelog configuration at thecarbon atom R₁₁ is bonded to is (S).
 194. The compound of claim 149,wherein each of R₁, R₂, and R₃ is H; R₄ is H; R₆ is C₁₋₆ alkyloptionally substituted with one or more substituents selected from thegroup consisting of halogen and OR^(a); R₉ is fluoro, R₁₀ is chloro, andR₁₁ is methyl.
 195. The compound of any one of claims 149 and 194,wherein each of R₁, R₂, and R₃ is H; R₄ is H; R₆ is H or C₁₋₆ alkyl; R₉is fluoro, R₁₀ is chloro, R₁₁ is methyl, and wherein theCahn-Ingold-Prelog configuration at the carbon atom R is bonded to is(S).
 196. A compound of Formula (IIB):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: R₉ is selected from H and halogen; R₁₀ isselected from H, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₆cycloalkyl; R₁₁ is selected from C₁₋₃ alkyl, C₂₋₄ alkenyl, and C₃₋₆cycloalkyl, wherein the C₁₋₃ alkyl is optionally substituted with one ormore R^(b); each R^(b) is independently selected from OR^(c),—C(O)OR^(c), and —(O)aryl, wherein the aryl is optionally substitutedwith one or more R^(d); each R^(c) is independently selected fromhydrogen, C₁₋₃ alkyl, OH, O(C₁₋₃ alkyl), NO₂, —C(O)aryl, and aryl; andeach R^(d) is C₁₋₃ alkyl.
 197. The compound of claim 196, wherein one ofR₉ and R₁₀ is halogen and the other is H.
 198. The compound of claim196, wherein each of R₉ and R₁₀ is halogen.
 199. The compound of any oneof claims 196 and 198, wherein R₉ is fluoro and R₁₀ is chloro.
 200. Thecompound of any one of claim 196, wherein R₉ is H and R₁₀ is C₁₋₄ alkyl.201. The compound of any one of claim 196, wherein R₉ is halogen and R₁₀is C₁₋₄ alkyl.
 202. The compound of any one of claims 196 and 201,wherein R₉ is chloro and R₁₀ is C₁₋₄ alkyl.
 203. The compound of any oneof claims 196 and 201, wherein R₉ is fluoro and R₁₀ is C₁₋₄ alkyl. 204.The compound of any one of claims 196 and 200-203, wherein R₁₀ is ethyl.205. The compound of any one of claims 196 and 200-203, wherein R₁₀ isisopropyl.
 206. The compound of claim 196, wherein R₉ is H and R₁₀ isC₃₋₆ cycloalkyl.
 207. The compound of any one of claims 196 and 206,wherein R₁₀ is cyclopropyl.
 208. The compound of any one of claims 196and 206, wherein R₁₀ is cyclopentyl.
 209. The compound of any one ofclaims 196-208, wherein R₁₁ is selected from C₁₋₃ alkyl optionallysubstituted with one or more R^(b), and C₂₋₄ alkenyl.
 210. The compoundof any one of claims 196-208, wherein R₁₁ is selected from C₁₋₃ alkyloptionally substituted with one or more R^(b), and C₃₋₆ cycloalkyl. 211.The compound of any one of claims 196-210, wherein R₁₁ is C₁₋₃ alkyloptionally substituted with one or more R^(b).
 212. The compound of anyone of claims 196 and 209-211, wherein R^(b) is OR^(c), and whereinR^(c) is selected from H and C₁₋₃ alkyl.
 213. The compound of claim 212,wherein R^(c) is H.
 214. The compound of claim 212, wherein R^(c) isC₁₋₃ alkyl.
 215. The compound of any one of claims 196-211, wherein R₁₁is C₁₋₃ alkyl.
 216. The compound of any one of claims 196-211 and 215,wherein R₁₁ is methyl.
 217. The compound of any one of claims 196-208and 210, wherein R₁₁ is C₃₋₆ cycloalkyl.
 218. The compound of any one ofclaims 196-208, 210, and 217, wherein R₁₁ is cyclopropyl.
 219. Thecompound of any one of claims 196-218, wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₁ is bonded to is (R).
 220. Thecompound of any one of claims 196-219, wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₁ is bonded to is (S).
 221. Thecompound of claim 196, wherein each of R₉ and R₁₀ is halogen, and R₁₁ isC₁₋₃ alkyl optionally substituted with one or more R^(b).
 222. Thecompound of any one of claims 196 and 221, wherein R₉ is fluoro, R₁₀ ischloro, and R₁₁ is C₁₋₃ alkyl optionally substituted with one or moreR^(b).
 223. The compound of any one of claims 196, 221, and 222, whereinR₉ is fluoro, R₁₀ is chloro, and R₁₁ is methyl.
 224. The compound of anyone of claims 196 and 221-223, wherein R₉ is fluoro, R₁₀ is chloro, R₁₁is methyl, and wherein the Cahn-Ingold-Prelog configuration at thecarbon atom R₁₁ is bonded to is (S).
 225. A compound of Formula (III):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: R₁ is selected from H and C₁₋₃ alkyl; R₂is selected from H and C₁₋₃ alkyl; R₃ is selected from H and C₁₋₃ alkyl;or R₂ and R₃ together with the nitrogen atoms to which they are attachedand the carbon atom connecting the two nitrogen atoms form a 5- or6-membered ring; R₄ is selected from H and C₁₋₃ alkyl; R₅ is selectedfrom H and C₁₋₆ alkyl; R₆ is selected from H, C₁₋₆ alkyl, and C₂₋₆alkenyl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents selected from the group consisting of halogen, OR^(a),SR^(a), —C(O)OR^(a), and —SC(NH)NH₂; R₇ is selected from H and C₁₋₆alkyl; or R₆ and R₇ together with the carbon and nitrogen atoms to whichthey are attached form a ring having one of the formulas:

wherein the ring is optionally substituted on a carbon atom with C₁₋₆alkyl, wherein the C₁₋₆ alkyl is optionally substituted with one or moreOH; or R₅ and R₇ together with the carbon atoms to which they areattached and the nitrogen atom connecting the two carbon atoms form aring having one of the formulas:

R₈ is selected from H and halogen; R₁₂ is selected from H, halogen, andC₁₋₆ alkyl; R₁₃ is selected from H, halogen, C₁₋₆ alkyl, OR^(c),N(R^(c))₂, wherein C₁₋₆ alkyl is optionally substituted with one or moreof OR^(c) and aryl; R₁₄ is selected from H and aryl; or R₁₃ and R₁₄together with the carbon atoms to which they are attached form a 5- or6-membered cycloalkyl ring; R₁₅ is selected from H, C₁₋₆ alkyl, whereinthe C₁₋₆ alkyl is optionally substituted with one or more R^(b); eachR^(a) is independently selected from H and C₁₋₆ alkyl; each R^(b) isindependently selected from C₂₋₆ alkenyl, OR^(c), N(R^(c))₂,—C(O)OR^(c), C₃₋₆ cycloalkyl, and aryl; each R^(c) is independentlyselected from hydrogen, C₁₋₆ alkyl, aryl, and —(CH₂)aryl, wherein theC₁₋₆ alkyl and the aryl are each optionally substituted with one or moreR^(d); and each R^(d) is independently selected from OH, O(C₁₋₃ alkyl),NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.
 226. The compound of claim 225,wherein each of R₁, R₂, and R₃ is H.
 227. The compound of claim 225,wherein two of R₁, R₂, and R₃ are H, and the other is C₁₋₃ alkyl. 228.The compound of any one of claims 225 and 227, wherein two of R₁, R₂,and R₃ are H, and the other is methyl.
 229. The compound of claim 225,wherein one of R₁, R₂, and R₃ is H, and the other two are C₁₋₃ alkyl.230. The compound of any one of claims 225 and 229, wherein one of R₁,R₂, and R₃ is H, and the other two are methyl.
 231. The compound of anyone of claims 225-230, wherein R₄ is H.
 232. The compound of any one ofclaims 225-231, wherein R₆ is selected from H or C₁₋₆ alkyl optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, OR^(a), SR^(a), —C(O)OR^(a), or —SC(NH)NH₂. 233.The compound of any one of claims 225-232, wherein R₆ is H.
 234. Thecompound of any one of claims 225-233, wherein R₈ is H.
 235. Thecompound of any one of claims 225-234, wherein each of R₁₂ and R₁₃ is H.236. The compound of any one of claims 225-234, wherein each of R₁₂ andR₁₃ is not H.
 237. The compound of any one of claims 225-234, whereinone of R₁₂ and R₁₃ is H, and the other is not H.
 238. The compound ofany one of claims 225-234 and 237, wherein R₁₂ is H, and R₁₃ is C₁₋₆alkyl optionally substituted with one or more of OR^(c) or aryl. 239.The compound of any one of claims 225-234 and 237-238, wherein R₁₂ is H,and R₁₃ is C₁₋₆ alkyl optionally substituted with OR.
 240. The compoundof any one of claims 225-234 and 237-239, wherein R₁₂ is H, and R₁₃ isC₁₋₆ alkyl.
 241. The compound of any one of claims 225-234 and 237-240,wherein R₁₂ is H, and R₁₃ is halogen.
 242. The compound of any one ofclaims 225-234 and 237-241, wherein R₁₂ is H, and R₁₃ is fluoro. 243.The compound of any one of claims 225-234 and 236, wherein each of R₁₂and R₁₃ is C₁₋₆ alkyl.
 244. The compound of any one of claims 225-234and 236, wherein each of R₁₂ and R₁₃ is halogen.
 245. The compound ofany one of claims 225-234, 236, and 244, wherein each of R₁₂ and R₁₃ isfluoro.
 246. The compound of any one of claims 225-234 and 237, whereinR₁₂ is H, and R₁₃ is OR.
 247. The compound of any one of claims 225-234and 237, wherein R₁₂ is H, and R₁₃ is N(R^(c))₂.
 248. The compound ofany one of claims 246 and 247, wherein each R^(c) is selected from H orC₁₋₆ alkyl.
 249. The compound of any one of claims 246 and 247, whereineach R^(c) is selected from C₁₋₆ alkyl or —(CH₂)aryl.
 250. The compoundof any one of claims 246, 247, and 248, wherein each R^(c) is H. 251.The compound of any one of claims 246 and 247-249, wherein each R^(c) isC₁₋₆ alkyl.
 252. The compound of any one of claims 246, 247-249, and251, wherein each R^(c) is methyl.
 253. The compound of any one ofclaims 246, 247, and 249, wherein each R^(c) is —(CH₂)aryl.
 254. Thecompound of any one of claim 247, wherein one R^(c) is H and the otherR^(c) is C₁₋₆ alkyl.
 255. The compound of any one of claims 225-254,wherein the Cahn-Ingold-Prelog configuration at the carbon atom R₁₃ isbonded to is (R).
 256. The compound of any one of claims 225-254,wherein the Cahn-Ingold-Prelog configuration at the carbon atom R₁₃ isbonded to is (S).
 257. The compound of any one of claims 225-256,wherein R₁₄ is H.
 258. The compound of any one of claims 225-256,wherein R₁₄ is aryl.
 259. The compound of any one of claims 225-258,wherein the Cahn-Ingold-Prelog configuration at the carbon atom R₁₄ isbonded to is (R).
 260. The compound of any one of claims 225-258,wherein the Cahn-Ingold-Prelog configuration at the carbon atom R₁₄ isbonded to is (S).
 261. The compound of any one of claims 225-260,wherein R₁₅ is H.
 262. The compound of any one of claims 225-261,wherein R₁₅ is C₁₋₆ alkyl optionally substituted with one or more R^(b).263. The compound of any one of claims 225-261, wherein R₁₅ is C₁₋₆alkyl optionally substituted with one R^(b).
 264. The compound of anyone of claims 225-263, wherein R₁₅ is C₄₋₅ alkyl optionally substitutedwith one R^(b).
 265. The compound of any one of claims 262-264, whereinR^(b) is selected from OR^(c), N(R^(c))₂, and cyclopropyl.
 266. Thecompound of any one of claims 262-265, wherein R^(b) is N(R^(c))₂. 267.The compound of any one of claims 262-266, wherein R^(b) is NH₂.
 268. Acompound of Formula (IIIA):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: R₁ is selected from H and C₁₋₃ alkyl; R₂is selected from H and C₁₋₃ alkyl; R₃ is selected from H and C₁₋₃ alkyl;R₄ is selected from H and C₁₋₃ alkyl; R₆ is selected from H, C₁₋₆ alkyl,and C₂₋₆ alkenyl, wherein the C₁₋₆ alkyl is optionally substituted withone or more substituents selected from the group consisting of halogen,OR^(a), SR^(a), —C(O)OR^(a), and —SC(NH)NH₂; R₈ is selected from H andhalogen; R₁₂ is selected from H, halogen, and C₁₋₆ alkyl; R₁₃ isselected from H, halogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂, wherein C₁₋₆alkyl is optionally substituted with one or more of OR^(c) and aryl; R₁₄is selected from H and aryl; or R₁₃ and R₁₄ together with the carbonatoms to which they are attached form a 5- or 6-membered cycloalkylring; R₁₆ is C₁₋₆ alkyl; each R^(a) is independently selected from H andC₁₋₆ alkyl; each R^(c) is independently selected from hydrogen, C₁₋₆alkyl, aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl and the aryl areeach optionally substituted with one or more R^(d); and each R^(d) isindependently selected from OH, O(C₁₋₃ alkyl), NH₂, NH(C₁₋₃ alkyl), andN(C₁₋₃ alkyl)₂.
 269. The compound of claim 268, wherein each of R₁, R₂,and R₃ is H.
 270. The compound of claim 268, wherein two of R₁, R₂, andR₃ are H, and the other is C₁₋₃ alkyl.
 271. The compound of any one ofclaims 268 and 270, wherein two of R₁, R₂, and R₃ are H, and the otheris methyl.
 272. The compound of claim 268, wherein one of R₁, R₂, and R₃is H, and the other two are C₁₋₃ alkyl.
 273. The compound of any one ofclaims 268 and 272, wherein one of R₁, R₂, and R₃ is H, and the othertwo are methyl.
 274. The compound of any one of claims 268-273, whereinR₄ is H.
 275. The compound of any one of claims 268-274, wherein R₆ isselected from H or C₁₋₆ alkyl optionally substituted with one or moresubstituents selected from the group consisting of halogen, OR^(a),SR^(a), —C(O)OR^(a), or —SC(NH)NH₂.
 276. The compound of any one ofclaims 268-275, wherein R₆ is H.
 277. The compound of any one of claims268-276, wherein R₈ is H.
 278. The compound of any one of claims268-277, wherein each of R₁₂ and R₁₃ is H.
 279. The compound of any oneof claims 268-277, wherein each of R₁₂ and R₁₃ is not H.
 280. Thecompound of any one of claims 268-277, wherein one of R₁₂ and R₁₃ is H,and the other is not H.
 281. The compound of any one of claims 268-277,wherein R₁₂ is H, and R₁₃ is C₁₋₆ alkyl optionally substituted with oneor more of OR^(c) or aryl.
 282. The compound of any one of claims268-277 and 281, wherein R₁₂ is H, and R₁₃ is C₁₋₆ alkyl optionallysubstituted with OR^(c).
 283. The compound of any one of claims 268-277,281, and 282, wherein R₁₂ is H, and R₁₃ is C₁₋₆ alkyl.
 284. The compoundof any one of claims 268-277 and 280, wherein R₁₂ is H, and R₁₃ ishalogen.
 285. The compound of any one of claims 268-277, 280, and 284,wherein R₁₂ is H, and R₁₃ is fluoro.
 286. The compound of any one ofclaims 268-277 and 279, wherein each of R₁₂ and R₁₃ is C₁₋₆ alkyl. 287.The compound of any one of claims 268-277 and 279, wherein each of R₁₂and R₁₃ is halogen.
 288. The compound of any one of claims 268-277 and279, wherein each of R₁₂ and R₁₃ is fluoro.
 289. The compound of any oneof claims 268-277 and 280, wherein R₁₂ is H, and R₁₃ is OR.
 290. Thecompound of any one of claims 268-277 and 280, wherein R₁₂ is H, and R₁₃is N(R^(c))₂.
 291. The compound of any one of claims 289 and 290,wherein each R^(c) is selected from H or C₁₋₆ alkyl.
 292. The compoundof any one of claims 289 and 290, wherein R^(c) is selected from C₁₋₆alkyl or —(CH₂)aryl.
 293. The compound of any one of claims 289 and 290,wherein R^(c) is H.
 294. The compound of any one of claims 289 and 290,wherein R^(c) is C₁₋₆ alkyl.
 295. The compound of any one of claims 289and 290, wherein R^(c) is methyl.
 296. The compound of any one of claims289 and 290, wherein R^(c) is —(CH₂)aryl.
 297. The compound of claim290, wherein one R^(c) is H and the other R^(c) is C₁₋₆ alkyl.
 298. Thecompound of any one of claims 268-297, wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₃ is bonded to is (R).
 299. Thecompound of any one of claims 268-297, wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₃ is bonded to is (S).
 300. Thecompound of any one of claims 268-299, wherein R₁₄ is H.
 301. Thecompound of any one of claims 268-299, wherein R₁₄ is aryl.
 302. Thecompound of any one of claims 268-301, wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₄ is bonded to is (R).
 303. Thecompound of any one of claims 268-301, wherein the Cahn-Ingold-Prelogconfiguration at the carbon atom R₁₄ is bonded to is (S).
 304. Thecompound of any one of claims 268-303, wherein R₁₆ is C₁₋₆ alkyl. 305.The compound of any one of claims 268-304, wherein R₁₆ is methyl. 306.The compound of any one of claims 268-305, wherein theCahn-Ingold-Prelog configuration at the carbon atom R₁₆ is bonded to is(S).
 307. The compound of any one of claims 268-305, wherein theCahn-Ingold-Prelog configuration at the carbon atom R₁₆ is bonded to is(R).
 308. A compound of Formula (IIIB):

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein: R₁₂ is selected from H, halogen, and C₁₋₆alkyl; R₁₃ is selected from H, halogen, C₁₋₆ alkyl, OR^(c), N(R^(c))₂,wherein C₁₋₆ alkyl is optionally substituted with one or more of OR^(c)and aryl; R₁₆ is C₁₋₆ alkyl; each R^(c) is independently selected fromhydrogen, C₁₋₆ alkyl, aryl, and —(CH₂)aryl, wherein the C₁₋₆ alkyl andthe aryl are each optionally substituted with one or more R^(d); andeach R^(d) is independently selected from OH, O(C₁₋₃ alkyl), NH₂,NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂.
 309. The compound of claim 308,wherein each of R₁₂ and R₁₃ is H.
 310. The compound of claim 308,wherein each of R₁₂ and R₁₃ is not H.
 311. The compound of claim 308,wherein one of R₁₂ and R₁₃ is H, and the other is not H.
 312. Thecompound of any one of claims 308 and 311, wherein R₁₂ is H, and R₁₃ isC₁₋₆ alkyl optionally substituted with one or more of OR^(c) or aryl.313. The compound of any one of claims 308 and 311-312, wherein R₁₂ isH, and R₁₃ is C₁₋₆ alkyl optionally substituted with OR^(c).
 314. Thecompound of any one of claims 308 and 311-313, wherein R₁₂ is H, and R₁₃is C₁₋₆ alkyl.
 315. The compound of any one of claims 308 and 311,wherein R₁₂ is H, and R₁₃ is halogen.
 316. The compound of any one ofclaims 308, 311, 315, wherein R₁₂ is H, and R₁₃ is fluoro.
 317. Thecompound of any one of claims 308 and 310, wherein each of R₁₂ and R₁₃is C₁₋₆ alkyl.
 318. The compound of any one of claims 308 and 310,wherein each of R₁₂ and R₁₃ is halogen.
 319. The compound of any one ofclaims 308, 310, and 318, wherein each of R₁₂ and R₁₃ is fluoro. 320.The compound of any one of claims 308 and 311, wherein R₁₂ is H, and R₁₃is OR^(c).
 321. The compound of any one of claims 308 and 311, whereinR₁₂ is H, and R₁₃ is N(R^(c))₂.
 322. The compound of any one of claims320 and 321, wherein each R^(c) is selected from H or C₁₋₆ alkyl. 323.The compound of any one of claims 320 and 321, wherein each R^(c) isselected from C₁₋₆ alkyl or —(CH₂)aryl.
 324. The compound of any one ofclaims 320 and 321, wherein each R^(c) is H.
 325. The compound of anyone of claims 320 and 321, wherein each R^(c) is C₁₋₆ alkyl.
 326. Thecompound of any one of claims 320 and 321, wherein each R^(c) is methyl.327. The compound of any one of claims 320 and 321, wherein each R^(c)is —(CH₂)aryl.
 328. The compound of claim 321, wherein one R^(c) is Hand the other R^(c) is C₁₋₆ alkyl.
 329. The compound of any one ofclaims 308-328, wherein the Cahn-Ingold-Prelog configuration at thecarbon atom R₁₃ is bonded to is (R).
 330. The compound of any one ofclaims 308-328, wherein the Cahn-Ingold-Prelog configuration at thecarbon atom R₁₃ is bonded to is (S).
 331. The compound of any one ofclaims 308-330, wherein R₁₆ is C₁₋₆ alkyl.
 332. The compound of any oneof claims 308-331, wherein R₁₆ is methyl.
 333. The compound of any oneof claims 308-332, wherein the Cahn-Ingold-Prelog configuration at thecarbon atom R₁₆ is bonded to is (S).
 334. The compound of any one ofclaims 308-332, wherein the Cahn-Ingold-Prelog configuration at thecarbon atom R₁₆ is bonded to is (R).
 335. The compound of claim 308,wherein one of R₁₂ and R₁₃ is H, and the other of R₁₂ and R₁₃ is not H;and R₁₆ is methyl, wherein the Cahn-Ingold-Prelog configuration at thecarbon atom R₁₆ is bonded to is (S).
 336. The compound of any one ofclaims 308 and 335, wherein R₁₂ is H, and R₁₃ is OR^(c); R^(c) isselected from H or C₁₋₆ alkyl; and R₁₆ is methyl, wherein theCahn-Ingold-Prelog configuration at the carbon atom R₁₆ is bonded to is(S).
 337. A compound selected from any one of the compounds listed inTable 1, or a tautomer thereof or a pharmaceutically acceptable salt ofthe compound or tautomer.
 338. A pharmaceutical composition comprising acompound of any one of claims 1-337, or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer, and apharmaceutically acceptable carrier.
 339. A method of treating amicrobial infection comprising administering to a subject in needthereof an effective amount of a compound of any one of claims 1-337, ora tautomer thereof or a pharmaceutically acceptable salt of the compoundor tautomer, or a pharmaceutically acceptable composition of claim 338.340. A method of preventing a microbial infection comprisingadministering to a subject in need thereof an effective amount of acompound of any one of claims 1-337, or a tautomer thereof or apharmaceutically acceptable salt of the compound or tautomer, or apharmaceutically acceptable composition of claim
 338. 341. A method ofreducing the risk of a microbial infection comprising administering to asubject in need thereof an effective amount of a compound of any one ofclaims 1-337, or a tautomer thereof or a pharmaceutically acceptablesalt of the compound or tautomer, or a pharmaceutically acceptablecomposition of claim
 338. 342. A method of delaying the onset of amicrobial infection comprising administering to a subject in needthereof an effective amount of a compound of any one of claims 1-337, ora tautomer thereof or a pharmaceutically acceptable salt of the compoundor tautomer, or a pharmaceutically acceptable composition of claim 338.343. Use of a compound according to any one of claims 1-337, or atautomer thereof or a pharmaceutically acceptable salt of the compoundor tautomer, in the manufacture of a medicament for treating,preventing, or reducing a microbial infection in a subject.
 344. Acompound according to any one of claims 1-337, or a tautomer thereof ora pharmaceutically acceptable salt of the compound or tautomer, for usein treating, preventing, or reducing a microbial infection in a subject.